Myocardial infarction(MI)is the leading cause of cardiovascular disease-related death worldwide.Nonetheless,existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and ...Myocardial infarction(MI)is the leading cause of cardiovascular disease-related death worldwide.Nonetheless,existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence.Caffeic acid(CA)is a bioactive polyphenolic compound with important anti-inflammatory,anti-bacterial and anti-oxidant functions.Still,its specific role and mechanism in treating cardiovascular disease remain to be further studied.In recent years,a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2(Keap1/Nrf2)pathway is a key factor in the occurrence and development of cardiovascular diseases.In this study,H2O2-induced oxidative stress model of H9c2 cells and left anterior descending branch(LAD)conjunctival induced acute myocardial infarction reperfusion(AMI/R)model were used to evaluate the protective effect of CA on the heart.The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe,target fishing,isothermal titration calorimetry(ITC),protein crystallography and surface plasmon resonance(SPR).Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner,further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress.In addition,based on the three-dimensional eutectic structure,it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532,inducing conformation changes in Keap1 protein.We also found that the CA analog chlorogenic acid(GCA)can bind Keap1.In conclusion,this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.展开更多
PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apop...PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.展开更多
Objective:To investigate the potential protective effect of Shexiang Tongxin dropping pills(STDP)on ischemia-reperfusion injury and its underlying mechanisms in improving endothelial cell function in coronary microvas...Objective:To investigate the potential protective effect of Shexiang Tongxin dropping pills(STDP)on ischemia-reperfusion injury and its underlying mechanisms in improving endothelial cell function in coronary microvascular disease(CMVD).Methods:A rat model of myocardial ischemia-reperfusion injury with CMVD was established using ligation and reperfusion of the left anterior descending artery.The effect of STDP(21.6 mg/kg)on cardiac function was evaluated using echocardiography,hematoxylin-eosin staining,and Evans blue staining.The effects of STDP on the microvascular endothelial barrier were assessed based on nitric oxide production,endothelial nitric oxide synthase expression,structural variety of tight junctions(TJs),and the expression of zonula occludens-1(ZO-1),claudin-5,occludin,and vascular endothelial(VE)-cadherin proteins.The mechanisms of STDP(50 and 100 ng/mL)were evaluated by examining the expression of sphingosine 1-phosphate receptor 2(S1PR2),Ras Homolog family member A(RhoA),and Rho-associated coiled-coil-containing protein kinase(ROCK)proteins and the distribution of ZO-1,VE-cadherin,and Factin proteins in an oxygen and glucose deprivation/reoxygenation model.Results:The administration of STDP on CMVD rat model significantly improved cardiac and microvascular endothelial cell barrier functions(all P<.05).STDP enhanced the structural integrity of coronary microvascular positioning and distribution by clarifying and completing TJs and increasing the expression of ZO-1,occludin,claudin-5,and VE-cadherin in vivo(all P<.05).The S1PR2/RhoA/ROCK pathway was inhibited by STDP in vitro,leading to the regulation of endothelial cell TJs,adhesion junctions,and cytoskeletal morphology.Conclusion:STDP showed protective effects on cardiac impairment and microvascular endothelial barrier injury in CMVD model rats induced by myocardial ischemia-reperfusion injury through the modulation of the S1PR2/RhoA/ROCK pathway.展开更多
Curculigo orchioides(CUR)and Epimedium(EPI)are traditional Chinese medicines with estrogen-like biological activity,called Xianmao and Xianlingpi(Er-xian)in Chinese.However,whether Er-xian exerts protective effects on...Curculigo orchioides(CUR)and Epimedium(EPI)are traditional Chinese medicines with estrogen-like biological activity,called Xianmao and Xianlingpi(Er-xian)in Chinese.However,whether Er-xian exerts protective effects on myocardial ischemia-reperfusion injury(MIRI)is unknown.This study aimed to investigate the cardioprotective effects of Er-xian preconditioning against MIRI and the underlying mechanisms.CUR or EPI was administered intragastrically to aged female rats as a monotherapy or combination therapy.2 weeks later,a rat MIRI model was established.Myocardial infarction size,myocardial morphology,cTnT,cell apoptosis rate,intracellular calcium concentration,mitochondrial permeability transition pore(MPTP)opening and reperfusion injury salvage kinase(RISK)signaling pathway molecules were observed after the surgery.To evaluate the mechanisms of Er-xian,estrogen receptors antagonists ICI 182780 and G15 were used.In this study,Er-xian notably alleviated myocardial tissue damage,maintained mitochondrial morphology,reduced infarct size and cardiac markers,and increased sera levels of E2.Moreover,Er-xian inhibited calcium overload and mPTP opening,and decreased cardiomyocyte apoptosis.We found that the dual therapy of CUR and EPI elicited more noticeable results than CUR or EPI monotherapy.The significant protective effects of Er-xian on ischemia-reperfusion myocardium were attributed to the up-regulation of AKT,ERK1/2 and GSK-3βphosphorylation levels.The cardioprotective effects of Er-xian were significantly reduced after estrogen receptor blockade,especially GPER30.These results indicate that Er-xian attenuates MIRI through RISK signaling pathway and estrogen receptors are the critical mediators.展开更多
Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;howe...Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.展开更多
Objective To investigate the protective effects of Jiawei Danshen Decoction(加味丹参饮,JWDSD)on myocardial ischemia-reperfusion injury(MIRI)via the regulation of serum Hydrogen sulfide(H2S)and cardiac Beclin1,light Ch...Objective To investigate the protective effects of Jiawei Danshen Decoction(加味丹参饮,JWDSD)on myocardial ischemia-reperfusion injury(MIRI)via the regulation of serum Hydrogen sulfide(H2S)and cardiac Beclin1,light Chain 3 A/B(LC3 A/B),p62,and autophagy protein5(ATG5).Methods Seventy specific pathogen free(SPF)Sprague-Dawley(SD)rats were randomly assigned to seven groups(n=10 in each group),including normal control,sham operation,MIRI model(model),ischemic preconditioning,Na HS,JWDSD,and JWDSD+CSE inhibitor(JWDSD+PPG)groups,and orally administered the indicated drugs for 14 d.Two hours after the last administration,the left anterior decreased branch of the coronary artery of each rat in model,Na HS,JWDSD,and JWDSD+PPG groups was ligated for 30 min and subsequently reperfused for 90 min to establish the MIRI model,and the rats in the sham operation group were only exposed to the thorax after surgery without coronary ligation.Blood samples were collected to detect H2S levels using an enzyme-linked immunosorbent assay(ELISA).Heart tissues were harvested for histopathological and immunohistochemical examination and quantitative reverse transcription polymerase chain reaction analysis of Beclin1 and ATG5 m RNA expression and Western blot analysis of Beclin1,LC3 A/B,and p62 protein expression.Results(1)The serum H2S content in model group rats was significantly reduced(P<0.01),JWDSD significantly increased the serum H2S content of model group rats(P<0.01),and the CSE inhibitor(PPG)significantly reduced H2S levels in the JWDSD group rats(P<0.01).(2)Compared with the normal control group,the myocardial tissue necrosis and cell destruction occurred in the MIRI model group,and JWDSD could alleviate the myocardial tissue necrosis of model rats,but the ameliorative effect of JWDSD could be reversed by PPG.(3)Beclin1,LC3 A/B,and p62 expression levels in the heart tissues of the model group were significantly increased(P<0.001),whereas decreased by JWDSD(P<0.05,P<0.01,and P<0.001,respectively),and the inhibitory effects of JWDSD on Beclin1,LC3 A/B,and p62 expression were partially reversed by PPG(P<0.01,P<0.05,and P<0.01,respectively).(4)The expression levels of autophagy-related genes Beclin1 and ATG5 were significantly increased in the model group(P<0.001).JWDSD clearly downregulated the expression levels of Beclin1 and ATG5(P<0.05 and P<0.001,respectively),which were reversed by PPG(P<0.001).Conclusion Our experimental data show that JWDSD can exhibit an anti-MIRI role by increasing endogenous H2S generation,and downregulating the expression of Beclin1,LC3 A/B,p62 and ATG5,which are related to inhibiting autophagy signaling.展开更多
This study examined the protective effect of ischemic postconditioning(IPoC) and minocycline postconditioning(MT) on myocardial ischemia-reperfusion(I/R) injury in atherosclerosis(AS) animals and the possible mechanis...This study examined the protective effect of ischemic postconditioning(IPoC) and minocycline postconditioning(MT) on myocardial ischemia-reperfusion(I/R) injury in atherosclerosis(AS) animals and the possible mechanism.Forty male healthy rabbits were injected with bovine serum albumin following feeding on a high fat diet for 6 weeks to establish AS model.AS rabbits were randomly divided into 3 groups:(1) I/R group,the rabbits were subjected to myocardial ischemia for 35 min and then reperfusion for 12 h;(2) IPoC group,the myocardial ischemia lasted for 35 min,and then reperfusion for 20 s and ischemia for 20 s [a total of 3 cycles(R20s/I20s×3)],and then reperfusion was sustained for 12 h;(3) MT group,minocycline was intravenously injected 10 min before reperfusion.The blood lipids,malondialdehyde(MDA),superoxide dismutase(SOD),soluble cell adhesion molecule(sICAM),myeloperoxidase(MPO),and cardiac troponin T(cTnT) were biochemically determined.The myocardial infarction size(IS) and apoptosis index(AI) were measured by pathological examination.The expression of bcl-2 and caspase-3 was detected in the myocardial tissue by using reverse transcription-polymerase chain reaction(RT-PCR).The results showed that the AS models were successfully established.The myocardial IS,the plasma levels of MDA,sICAM,MPO and cTnT,and the enzymatic activity of MPO were significantly decreased,and the plasma SOD activity was significantly increased in IPoC group and MT group as compared with I/R group(P<0.05 for all).The myocardial AI and the caspase-3 mRNA expression were lower and the bcl-2 mRNA expression was higher in IPoC and MT groups than those in I/R group(all P<0.05).It is concluded that the IPoC and MT can effectively reduce the I/R injury in the AS rabbits,and the mechanisms involved anti-oxidation,anti-inflammation,up-regulation of bcl-2 expression and down-regulation of caspase-3 expression.Minocycline can be used as an effective pharmacologic postconditioning drug to protect myocardia from I/R injury.展开更多
To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending(LAD)coronary artery,we first randomly divided 16 male Bama pigs into a sham...To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending(LAD)coronary artery,we first randomly divided 16 male Bama pigs into a sham group and a model group.After anesthesia,we separated the arteries and veins.Subsequently,we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision.Then,we loosened and released the ligation line after five minutes of pre-occlusion.Finally,we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia.Compared with the sham group,electrocardiogram showed multiple continuous lead ST-segment elevations,and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group.Twenty-four hours after the operation,cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group,compared with the sham group.Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group.Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group.All eight pigs in the model group recovered with normal sinus heart rates,and the survival rate was 100%.In conclusion,the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.展开更多
Background:Ischemia-reperfusion can worsen myocardial damage and increase the risk of death.Studies have revealed that ischemic preconditioning provides the best endogenous protection against myocardial ischemia-reper...Background:Ischemia-reperfusion can worsen myocardial damage and increase the risk of death.Studies have revealed that ischemic preconditioning provides the best endogenous protection against myocardial ischemia-reperfusion injury(MIRI),and the principle of electroacupuncture(EA)preconditioning is comparable to that of myocardial ischemic preconditioning adaption.Our earlier research demonstrated that EA pretreatment inhibits the expression of calmodulin-dependent protein kinase IIδ(CaMKIIδ),sodium/calcium exchanger 1(NCX1),and cyclophilin D,hence providing protection against MIRI.However,the exact mechanism is still unknown.The expression of NCX1 mRNA is directly regulated by microRNA-214(miR-214).Moreover,it suppresses the levels of CaMKIIδand cyclophilin D.Whether these variables contribute to EA preconditioning to improve MIRI needs to be investigated,though.This study aimed to preliminarily determine whether EA pretreatment ameliorates MIRI by modulating the miR-214-3p/NCX1 axis.Methods:We used a rat MIRI model to investigate the effect of EA pretreatment on MIRI and the expression of miR-214-3p.In addition,adenovirus injection inhibited miR-214-3p expression in the rat MIRI model,and the influence of EA pretreatment towards MIRI was observed in the context of blocked miR-214-3p expression.Both the myocardial histological abnormalities and the alterations in the ST segment of the rat electrocardiogram were analyzed.NCX1 mRNA,cyclophilin D,and CaMKIIδexpression levels were also analyzed.Results:EA pretreatment improved MIRI.In rats with MIRI,EA administration increased miR-214-3p expression while decreasing NCX1 mRNA,cyclophilin D,and CaMKIIδproteins in cardiac tissues.The beneficial effect of EA pretreatment against MIRI was reversed,coupled with elevated levels of NCX1 mRNA,cyclophilin D,and CaMKIIδprotein expression,when an adenovirus injection disrupted the expression of miR-214-3p.Conclusions:Our findings preliminarily show that EA pretreatment inhibits the expression of NCX1 mRNA,cyclophilin D,and CaMKIIδproteins via miR-214-3p,hence exerting MIRI protection.展开更多
Background Myocardial ischemia/reperfusion(I/R)injury remains a great challenge in clinical therapy.Recent studies indicated that circularRNA(circRNA)play an important role in the regulation of atherosclerotic heart d...Background Myocardial ischemia/reperfusion(I/R)injury remains a great challenge in clinical therapy.Recent studies indicated that circularRNA(circRNA)play an important role in the regulation of atherosclerotic heart disease.However,as a new circRNA,the effect of circRNA regulating ischemia-reperfusion through microRNA-1(CRIRTM)on myocardial apoptosis during myocardial ischemia/reperfusion is still unknown.The purpose of this study was to investigate the effect of CRIRTM on I/R-induced apoptosis and the expression of microRNA-1(miR-1)and calmodulin(CaM)in cultured neonatal rat ventricular cardiomyocytes(NRVCs)in vitro and SD rat hypoxia-reoxygenation model in vivo.Methods NRVCs were subjected to hypoxia for 30 minutes and then oxygen was added for 12 hours to establish the model of cell ischemia reperfusion.The SD rats were subjected to the surgery of ligating the anterior descending branch of the left coronary artery for 4 hours and then reperfused for 48 hours to establish myocardial ischemia animal model.The expression of CRIRTM,miIR-1 and CaM was detected by quantitative real-time polymerase chain reaction(qRT-PCR).TUNEL was used to analyze the apoptosis level of cells and animal myocardium after small interfering RNA(siRNA)down-regulation of CRIRTM.The expression of CRIRTM in the blood of patients with myocardial infarction was detected,and the downstream of CRIRTM was analyzed by Target Scan.Results The specific upregulation of CRIRTM was detected in the plasma of patients with ST-segment elevation myocardial infarction after reperfusion,and multiple binding sites between CRIRTM and miR-1 were found by Target Scan analysis.The expression of CRIRTM and CaM was up-regulated and the expression of miR-1 was down-regulated in cells and rats I/R model.Both in vivo and in vitro,cardiomyocyte apoptosis induced by myocardial ischemia-reperfusion will increase after down-regulation of CRIRTM.It may be due to the decreased inhibition of miR-1 by down-regulated CRIRTM,which increases the degradation of CaM by miR-1 and aggravates cardiomyocyte apoptosis.Conclusions Our data demonstrated that CRIRTM alleviates myocardial ischemia-reperfusion injury via suppressing miR-1 leading to enhanced CaM levels.[S Chin J Cardiol 2021;22(1):30-37]展开更多
BACKGROUND Myocardial ischemia-reperfusion injury(MIRI)poses a prevalent challenge in current reperfusion therapies,with an absence of efficacious interventions to address the underlying causes.AIM To investigate whet...BACKGROUND Myocardial ischemia-reperfusion injury(MIRI)poses a prevalent challenge in current reperfusion therapies,with an absence of efficacious interventions to address the underlying causes.AIM To investigate whether the extracellular vesicles(EVs)secreted by adipose mesenchymal stem cells(ADSCs)derived from subcutaneous inguinal adipose tissue(IAT)underγ-aminobutyric acid(GABA)induction(GABA-EVs^(IAT))demonstrate a more pronounced inhibitory effect on mitochondrial oxidative stress and elucidate the underlying mechanisms.METHODS We investigated the potential protective effects of EVs derived from mouse ADSCs pretreated with GABA.We assessed cardiomyocyte injury using terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/propidium iodide assays.The integrity of cardiomyocyte mitochondria morphology was assessed using electron microscopy across various intervention backgrounds.To explore the functional RNA diversity between EVs^(IAT)and GABA-EVs^(IAT),we employed microRNA(miR)sequencing.Through a dual-luciferase reporter assay,we confirmed the molecular mechanism by which EVs mediate thioredoxin-interacting protein(TXNIP).Western blotting and immunofluorescence were conducted to determine how TXNIP is involved in mediation of oxidative stress and mitochondrial dysfunction.RESULTS Our study demonstrates that,under the influence of GABA,ADSCs exhibit an increased capacity to encapsulate a higher abundance of miR-21-5p within EVs.Consequently,this leads to a more pronounced inhibitory effect on mitochondrial oxidative stress compared to EVs from ADSCs without GABA intervention,ultimately resulting in myocardial protection.On a molecular mechanism level,EVs regulate the expression of TXNIP and mitigating excessive oxidative stress in mitochondria during MIRI process to rescue cardiomyocytes.CONCLUSION Administration of GABA leads to the specific loading of miR-21-5p into EVs by ADSCs,thereby regulating the expression of TXNIP.The EVs derived from ADSCs treated with GABA effectively ameliorates mitochondrial oxidative stress and mitigates cardiomyocytes damage in the pathological process of MIRI.展开更多
Objective:To investigate the therapeutic effect of microRNA210(miRNA-210)modified mesenchymal stem cells(MSCs)on myocardial ischemia-reperfusion injury(MIRI)model rats.Methods:One SD rat was sacrificed,and the lower e...Objective:To investigate the therapeutic effect of microRNA210(miRNA-210)modified mesenchymal stem cells(MSCs)on myocardial ischemia-reperfusion injury(MIRI)model rats.Methods:One SD rat was sacrificed,and the lower extremity tibia and femur were isolated.MSCs were cultured by whole bone marrow adherence method to construct miRNA-210 modified MSCs.40 SD rats were divided into the sham operation group,model group,MSCs group,and miRNA-210+MSCs group,with 10 rats in each group.The left anterior descending coronary artery was ligated to prepare a model of myocardial ischemia and reperfusion.After successful modeling,50μl of MSCs suspension was injected into the tail vein of the MSCs group,and 50μl of miRNA-210 modified MSCs suspension was injected into the tail vein of the miRNA-210+MSCs group.The sham operation group and the model group were injected with the same amount of normal saline.On the 10th day after modeling,the area of myocardial infarction,morphological changes of myocardial tissue,myocardial cell apoptosis rate,and miRNA-210 expression were compared in each group.Results:The area of myocardial infarction and the rate of myocardial cell apoptosis in the model group were significantly higher than those in the sham operation group(<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the MSCs group were significantly lower than those in the sham operation group(P<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the miRNA-210+MSCs group were significantly higher than those in the MSCs group(P<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the miRNA-210+MSCs group were significantly lower than those in the sham operation group(P<0.05).The expression level of miRNA-210 in the myocardial tissue of the model group was significantly higher than that in the sham operation group(P<0.05);There were no significantly different in the expression level of miRNA-210 in the myocardial tissue between the MSCs group and model group(P>0.05);The expression level of miRNA-210 in the myocardial tissue of MSCs group was significantly higher than in the MSCs group,model group and sham operation group(P<0.05).HE staining showed that the miRNA-210+MSCs group had normal morphology of myocardial tissues,more uniform cytoplasmic staining,and arranged neatly myocardial fibers.The inflammatory cell infiltration and interstitial edema of the miRNA-210+MSCs group were significantly improved compared with the model group and MSCs group.Conclusion:MiRNA-210 modified MSCs can inhibit myocardial cell apoptosis in myocardial ischemia-reperfusion injury model rats,reduce the area of myocardial infarction,and improve pathological damage of myocardial tissue in rats,which has a certain therapeutic effect on myocardial ischemia-reperfusion injury.展开更多
Background:Currently,no drugs can specifically improve clinical cardiac ischemia-reperfusion injury or the prognosis of hemodialysis.Salvianolic acid B(SalB)is a widely used cardiac protectant;however,its clinical app...Background:Currently,no drugs can specifically improve clinical cardiac ischemia-reperfusion injury or the prognosis of hemodialysis.Salvianolic acid B(SalB)is a widely used cardiac protectant;however,its clinical application is limited by its low oral bioavailability and poor intestinal absorption.The exploration of its preparation and clinical applications has become a research hotspot in recent years.Methods:To determine whether mesoporous silica nanoparticles(MSNs)efficiently delivered SalB to the heart and SalB@MSNs-RhB reduced myocardial ischemia-reperfusion injury,we constructed a myocardial ischemia-reperfusion male rat model,hypoxia/reoxygenation cardiomyocytes,and treated them with SalB@MSNs-RhB.Results:SalB@MSNs-RhB showed improved bioavailability,therapeutic effect,heightened JAK2/STAT3-dependent pro-survival signaling,and antioxidant responses,thereby protecting cardiomyocytes from ischemia-reperfusion injury-induced oxidative stress and apoptosis.Conclusion:This use of SalB-loaded nanoparticles and investigation of their mechanism of action may provide a new strategy for treating cardiomyocytes.Thus,hypoxia/reoxygenation promotes the clinical application of SalB.展开更多
Purpose: Ischemia-reperfusion (I/R) injury exacerbates myocardial cell death (including apoptosis and necrosis), leading to complications such as arrhythmias, myocardial stenosis, microvascular obstruction and heart f...Purpose: Ischemia-reperfusion (I/R) injury exacerbates myocardial cell death (including apoptosis and necrosis), leading to complications such as arrhythmias, myocardial stenosis, microvascular obstruction and heart failure, and it is particularly important to seek new strategies to mitigate reperfusion injury. In this paper, we will investigate whether atorvastatin can alleviate myocardial ischemia-reperfusion injury and verify its molecular mechanism. Methods: We successfully constructed a hypoxia-reperfusion (H/R) H9c2 cell model and transfected miR-26a-5p mimic, miR-26a-5p inhibitor and its negative control NC-mimic or NC-inhibitor into H9c2 cells using a transfection kit. The expression of miR-26a-5p and FOXO1 were detected by RT-qPCR assay, the expression of related proteins by Western blot assay, the cell viability of H9c2 cells by CCK-8 assay, the apoptosis rate of H9c2 cells by flow cytometry, the CK and LDH activity in cells by CK and LDH assay kits. The targeting relationship between miR-26a-5p and FOXO1 was verified by dual luciferase reporter gene assay. Results: MiR-26a-5p expression was decreased in H/R-induced cells and FOXO1 expression was increased in H/R-induced cells. Atorvastatin alleviated H/R injury in cardiomyocytes and was most effective at a concentration of 1 μM. Atorvastatin alleviated H/R injury in cardiomyocytes by upregulating miR-26a-5p expression, miR-26a-5p and FOXO1 were negatively regulated by targeting. Conclusion: Atorvastatin can alleviate H/R injury in cardiomyocytes by regulating miR-26a-5p/FOXO1.展开更多
Background Myocardial ischemia-reperfusion injury is characterized by the inability of tissue and organ function to recover after the perfusion blood flow is restored followed by myocardial ischemia.Previous studies h...Background Myocardial ischemia-reperfusion injury is characterized by the inability of tissue and organ function to recover after the perfusion blood flow is restored followed by myocardial ischemia.Previous studies have shown that many Chinese herbal compounds can reduce myocardial ischemia-reperfusion injury,but the efficacy of Wuling Powder in treating myocardial ischemia-reperfusion injury has not been reported.The present study aimed to investigate the mechanism of Wuling Powder in treating myocardial ischemia-reperfusion injury by network pharmacology and molecular docking.Methods The active constituents of Wuling Powder were obtained by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and the related targets of active constituents of Wuling Powder were screened by the Swiss Target Prediction database.Disease targets of myocardial ischemia-reperfusion injury were obtained by Gene Cards,Dis Ge NET and OMIM gene databases.The active compound-target network of Wuling Powder was constructed using Cytoscape software.The drug prediction targets were mapped to the disease target set,and the intersection targets were obtained.The Gene Ontology(GO)function and Kyoto Encyclopedia of Genes anf Genomes(KEGG)pathway enrichment analysis were performed on the intersection targets obtained by using String database.Auto Dock Vina was used for molecular docking of core targets and the top 3 key active ingredients with degree values.Results Through screening,56 active ingredients and 116 targets of Wuling Powder were obtained.There were 27 common targets of Wuling Powder and myocardial ischemia-reperfusion injury in Myocardial ischemia-reperfusion injury(MIRI).Protein-Protein Interaction(PPI)network analysis in this study showed that CASP3,PTGS2,CAT,JUN,ESR1,CASP8,CASP9 and RELA may be the key targets of Wuling Powder to exert the protective effect of MIRI.GO functional analysis and KEGG pathway enrichment analysis showed that biological processes such as apoptosis,lipopolysaccharide response,steroid hormone response and signal transduction pathways such as PTGS2,TNF-α,nuclear transcription factor-κB(NF-κB),MAPK,PI3K/AKT,NLRP3,and autophagy play an important role in the occurrence and development of MIRI.Molecular docking results showed thatβ-sitosterol and hederagenin had good binding activities with key targets such as PTGS2,CASP3,and CAT.Conclusions Wuling Powder may act on CASP3,PTGS,CAT,JUN,ESR1,CASP8,CASP9 and other targets throughβ-sitosterol,hederagenin,3β-acetoxyatractylone,taxifolin and other active ingredients.[S Chin J Cardiol 2024;25(3):179-192]展开更多
Background Myocardial ischemia-reperfusion injury(MI/RI)is an important complication after reperfusion therapy in ischemic cardiomyopathy.Its pathogenesis is complex,and there is no effective prevention and treatment ...Background Myocardial ischemia-reperfusion injury(MI/RI)is an important complication after reperfusion therapy in ischemic cardiomyopathy.Its pathogenesis is complex,and there is no effective prevention and treatment measures.It has been confirmed that apoptosis,ferroptosis,pyroptosis and other different cell death forms are involved in the pathophysiological process of MI/RI.This article reviews the research progress of the above different forms of cell death in MI/RI in recent years,hoping to provide a new reference for the prevention and treatment of MI/RI.展开更多
Objective: To evaluate the myocardial protective effect of Gualou Xiebai Banxia decoction (瓜蒌薤白半夏汤GXBD) and explore the mechanisms of inhibition of NF-kappa B activation and blockade of inflammatory responses i...Objective: To evaluate the myocardial protective effect of Gualou Xiebai Banxia decoction (瓜蒌薤白半夏汤GXBD) and explore the mechanisms of inhibition of NF-kappa B activation and blockade of inflammatory responses induced by ischemia-reperfusion in rats. Methods: Twenty-four Sprague Dawley (SD) rats were randomly divided into three groups. Rats in the treatment group received GXBD (13 g crude drug/kg) for three weeks, while rats in the model control and normal control groups received equal volumes of distilled water. On the 22nd day, rats in the ischemia-reperfusion (I/R) control and GXBD-treated groups underwent 30 min occlusion of the left anterior descending (LAD) coronary artery, followed by 120 min reperfusion. Electrocardiogram was recorded, and the activities of cardiac enzymes, cytokines, and NF-кB were assessed after I/R. Results: Compared with the I/R control group, GXBD treatment restored the activity of the specific myocardial-injury marker creatine kinase (CK) and lactate dehydrogenase (LDH), and inhibited the inflammatory response involving the nuclear factor-кB (NF-кB) pathway, including down-regulation of interleukin (IL)-1β and IL-6, and up-regulation of IL-10 gene expression. Conclusion: GXBD strongly reduced myocardial impairment in our I/R model, including inhibition of NF-кB activation and inflammatory cytokine responses.展开更多
Our knowledge and understanding of the pathophysiology of coronary atherosclerosis has increased enormously over the last 20 years.Reperfusion through thrombolysis or percutaneous coronary angioplasty is the standard ...Our knowledge and understanding of the pathophysiology of coronary atherosclerosis has increased enormously over the last 20 years.Reperfusion through thrombolysis or percutaneous coronary angioplasty is the standard treatment for preventing acute myocardial infarction.Early reperfusion is an absolute prerequisite for survival of the ischemic myocardium,but reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone.These outcomes,in a range of reperfusion-associated pathologies,are collectively termed "reperfusion injuries".Reactive oxygen species are known to be produced in large quantities in the first few minutes of the post-ischemia reperfusion process.Similarly,scientific evidence from the last 15 years has suggested that melatonin has beneficial effects on the cardiovascular system.The presence of vascular melatoninergic receptor binding sites has been demonstrated;these receptors are functionally linked to vasoconstrictor or vasodilatory effects of melatonin.It has been shown that patients with coronary heart disease have a low melatonin production rate,especially those with higher risk of cardiac infarction and/or sudden death.Melatonin attenuates molecular and cellular damage resulting from cardiac ischemia-reperfusion in which destructive free radicals are involved.展开更多
A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial isc...A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion （I/R） injury. This tightly orchestrated cata-bolic cellular‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protec-tive mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the va-riability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin （mTOR） inhibitors, adenosine monophosphate-activated protein kinase （AMPK） modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic ma-nipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.展开更多
To explore mechanism and protective effect of rosiglitazone on myocardial ischemia reperfusion(I/R) injury.Methods:A total of 48 male Japanese white big-ear rabbits were randomly divided into control group(A),I/R grou...To explore mechanism and protective effect of rosiglitazone on myocardial ischemia reperfusion(I/R) injury.Methods:A total of 48 male Japanese white big-ear rabbits were randomly divided into control group(A),I/R group(B),low dose of rosiglitazone group(C),high dose of rosiglitazone group(D).Plasma concentration of and also reduced the concentration of plasma serum creatine kinase(CK),CK-MB.high-sensitivity C-reactive protein(hsCRP).ultrasuperoxide dismutase(SOD),malondialdehyde(MD.A).lactic acid glutathione skin peroxidase (C-SH-PX).nitric oxide(NO)and endothelin(ET) were measured 1 h later after I/R.Twenty-four hours after I/R the hearts were harvested for pathological and ultrastructural analysis.Area of myocardial infarction were tested.Results:Plasma concentration of CK,Ck-MB.hsCRP,NO. MDA and ET were decreased in C,D group compared with group B.Plasma concentration of T-SOD and GSH-Px were increased significantly in C.D group compared with group B.Compared with group B.pathological and ullraslructural changes in C and D group were slightly.There was significant difference in myocardial infarction area between group C.D and group B(P【0.05). Myocardial infarction area and arrhythmia rate were lower in group C,D compare with group B. Rosiglitazone may protect myocardium from I/R injury by enhancing T-SOD and GSH-Px concentration,inhibit inflammatory reaction,and improve endothelial function.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:81930114 and U22A20368)the National Key Research and Development Program of China(Grant No.:2017YFE0119900)Guangzhou Basic and Applied Basic Research Project(Project No.:202201011393).
文摘Myocardial infarction(MI)is the leading cause of cardiovascular disease-related death worldwide.Nonetheless,existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence.Caffeic acid(CA)is a bioactive polyphenolic compound with important anti-inflammatory,anti-bacterial and anti-oxidant functions.Still,its specific role and mechanism in treating cardiovascular disease remain to be further studied.In recent years,a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2(Keap1/Nrf2)pathway is a key factor in the occurrence and development of cardiovascular diseases.In this study,H2O2-induced oxidative stress model of H9c2 cells and left anterior descending branch(LAD)conjunctival induced acute myocardial infarction reperfusion(AMI/R)model were used to evaluate the protective effect of CA on the heart.The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe,target fishing,isothermal titration calorimetry(ITC),protein crystallography and surface plasmon resonance(SPR).Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner,further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress.In addition,based on the three-dimensional eutectic structure,it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532,inducing conformation changes in Keap1 protein.We also found that the CA analog chlorogenic acid(GCA)can bind Keap1.In conclusion,this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.
基金Natural Science Foundation of Guangxi(Grant No.2021JJD140147)。
文摘PI3K/AKT/mTOR signaling pathway is a key pathway of myocardial ischemia-reperfusion injury(MIRI).The mechanism of action is mainly oxidative stress,inflammatory response,calcium overload,ferroptosis,autophagy,and apoptosis.MIRI belongs to the category of chest obstruction in traditional Chinese medicine,and its etiology and pathogenesis are mainly“Yang Wei Yin Xian.”Traditional Chinese medicine has the effect of multi-target and multi-component effect,and has played a significant role in the treatment of MIRI in recent years.At present,the monomers of traditional Chinese medicine mainly include saponins,flavonoids,alkaloids,terpenoids,and phenols,and the compounds mainly include Zhigancao Decoction,Zhenyuan Capsule,Jiawei Shenqibai Powder,Qili Qiangxin Capsule,Tongmai Yangxin Pill,Zhilong Huoxue Tongyu Capsule,Guizhi Tongluo Tablets,etc.This paper reviews the research on the improvement of MIRI by regulating PI3K/AKT/mTOR signaling pathway in recent years,and expounds the mechanism and advantages of traditional Chinese medicine in the treatment of MIRI.
基金supported the National Natural Science Foundation of China(81930113).
文摘Objective:To investigate the potential protective effect of Shexiang Tongxin dropping pills(STDP)on ischemia-reperfusion injury and its underlying mechanisms in improving endothelial cell function in coronary microvascular disease(CMVD).Methods:A rat model of myocardial ischemia-reperfusion injury with CMVD was established using ligation and reperfusion of the left anterior descending artery.The effect of STDP(21.6 mg/kg)on cardiac function was evaluated using echocardiography,hematoxylin-eosin staining,and Evans blue staining.The effects of STDP on the microvascular endothelial barrier were assessed based on nitric oxide production,endothelial nitric oxide synthase expression,structural variety of tight junctions(TJs),and the expression of zonula occludens-1(ZO-1),claudin-5,occludin,and vascular endothelial(VE)-cadherin proteins.The mechanisms of STDP(50 and 100 ng/mL)were evaluated by examining the expression of sphingosine 1-phosphate receptor 2(S1PR2),Ras Homolog family member A(RhoA),and Rho-associated coiled-coil-containing protein kinase(ROCK)proteins and the distribution of ZO-1,VE-cadherin,and Factin proteins in an oxygen and glucose deprivation/reoxygenation model.Results:The administration of STDP on CMVD rat model significantly improved cardiac and microvascular endothelial cell barrier functions(all P<.05).STDP enhanced the structural integrity of coronary microvascular positioning and distribution by clarifying and completing TJs and increasing the expression of ZO-1,occludin,claudin-5,and VE-cadherin in vivo(all P<.05).The S1PR2/RhoA/ROCK pathway was inhibited by STDP in vitro,leading to the regulation of endothelial cell TJs,adhesion junctions,and cytoskeletal morphology.Conclusion:STDP showed protective effects on cardiac impairment and microvascular endothelial barrier injury in CMVD model rats induced by myocardial ischemia-reperfusion injury through the modulation of the S1PR2/RhoA/ROCK pathway.
基金This work was supported by the National Natural Science Foundation of China(No.81673787)the Science and Technology Plan Project of Xi'an City(No.2019114813YX003SF036-3)Scientific research project of Xi'an Health Committee(No.2021yb43).
文摘Curculigo orchioides(CUR)and Epimedium(EPI)are traditional Chinese medicines with estrogen-like biological activity,called Xianmao and Xianlingpi(Er-xian)in Chinese.However,whether Er-xian exerts protective effects on myocardial ischemia-reperfusion injury(MIRI)is unknown.This study aimed to investigate the cardioprotective effects of Er-xian preconditioning against MIRI and the underlying mechanisms.CUR or EPI was administered intragastrically to aged female rats as a monotherapy or combination therapy.2 weeks later,a rat MIRI model was established.Myocardial infarction size,myocardial morphology,cTnT,cell apoptosis rate,intracellular calcium concentration,mitochondrial permeability transition pore(MPTP)opening and reperfusion injury salvage kinase(RISK)signaling pathway molecules were observed after the surgery.To evaluate the mechanisms of Er-xian,estrogen receptors antagonists ICI 182780 and G15 were used.In this study,Er-xian notably alleviated myocardial tissue damage,maintained mitochondrial morphology,reduced infarct size and cardiac markers,and increased sera levels of E2.Moreover,Er-xian inhibited calcium overload and mPTP opening,and decreased cardiomyocyte apoptosis.We found that the dual therapy of CUR and EPI elicited more noticeable results than CUR or EPI monotherapy.The significant protective effects of Er-xian on ischemia-reperfusion myocardium were attributed to the up-regulation of AKT,ERK1/2 and GSK-3βphosphorylation levels.The cardioprotective effects of Er-xian were significantly reduced after estrogen receptor blockade,especially GPER30.These results indicate that Er-xian attenuates MIRI through RISK signaling pathway and estrogen receptors are the critical mediators.
基金supported by National Natural Science Foundation of China(Grant No.81860873 and 81960864)the Scientific and Technological Projects of Guizhou Province(Qian Kehe Jichu(2016)1401)High-level Talents Project of Guizhou Province(GUTCM(ZQ2018005)).
文摘Background:Liqi Huoxue dripping pill(LQHXDP),a traditional Chinese drug for coronary heart disease,has a protective effect on the heart of rats with myocardial ischemia-reperfusion injury(MIRI)in previous studies;however,its mechanism of action remains unclear.The purpose of this study was to investigate the protective mechanism of LQHXDP on MIRI in rats and its relationship with the PI3K/Akt signaling pathway.Methods:In this study,Sprague-Dawley rats were pre-infused with LQHXDP(175 mg/kg/d)for 10 days.PI3K inhibitor LY294002(0.3 mg/kg)was intravenously injected 15 minutes before ischemia.The rat model of MIRI was established by ligating the left anterior descending coronary artery.Subsequently,cardiac hemodynamics,serum myocardial injury markers,inflammatory factors,myocardial infarct size,antioxidant indexes,myocardial histopathology,and phosphorylation levels of key proteins of PI3K/Akt signaling pathway were assessed in rats.Results:LQHXDP was found to improve cardiac hemodynamic indexes,reduce serum creatine kinase MB isoenzyme activity and cardiac troponin and heart-type fatty acid binding protein levels,lower serum interleukin-1 beta,interleukin-6 and tumour necrosis factorαlevels,reduce the myocardial infarct size and enhance the antioxidant capacity of myocardial tissue in MIRI rats.Pathological analysis revealed that LQHXDP attenuated the extent of myocardial injury and protected mitochondria from damage in MIRI rats.Immunoblot analysis revealed that LQHXDP increased the expression levels of p-Akt and p-GSK-3βin MIRI rat cardiomyocytes.PI3K inhibitor LY294002 could impair these effects of LQHXDP.Conclusion:LQHXDP attenuated myocardial injury,attenuated oxidative stress injury and reduced inflammatory response in MIRI rats,and its protective effects were mediated by activating of PI3K/Akt/GSK-3βsignaling pathway.
基金funding support from the National Natural Science Foundation of China(No.81704065)Hunan Provincial Natural Science Foundation(No.2019JJ40225)+1 种基金the Scientific Research Project of Education Department of Hunan Province(No.19B415,No.19C1393 and No.20C1392)Hunan Provincial Scientific Research Project of Chinese Medicine(No.2020015)。
文摘Objective To investigate the protective effects of Jiawei Danshen Decoction(加味丹参饮,JWDSD)on myocardial ischemia-reperfusion injury(MIRI)via the regulation of serum Hydrogen sulfide(H2S)and cardiac Beclin1,light Chain 3 A/B(LC3 A/B),p62,and autophagy protein5(ATG5).Methods Seventy specific pathogen free(SPF)Sprague-Dawley(SD)rats were randomly assigned to seven groups(n=10 in each group),including normal control,sham operation,MIRI model(model),ischemic preconditioning,Na HS,JWDSD,and JWDSD+CSE inhibitor(JWDSD+PPG)groups,and orally administered the indicated drugs for 14 d.Two hours after the last administration,the left anterior decreased branch of the coronary artery of each rat in model,Na HS,JWDSD,and JWDSD+PPG groups was ligated for 30 min and subsequently reperfused for 90 min to establish the MIRI model,and the rats in the sham operation group were only exposed to the thorax after surgery without coronary ligation.Blood samples were collected to detect H2S levels using an enzyme-linked immunosorbent assay(ELISA).Heart tissues were harvested for histopathological and immunohistochemical examination and quantitative reverse transcription polymerase chain reaction analysis of Beclin1 and ATG5 m RNA expression and Western blot analysis of Beclin1,LC3 A/B,and p62 protein expression.Results(1)The serum H2S content in model group rats was significantly reduced(P<0.01),JWDSD significantly increased the serum H2S content of model group rats(P<0.01),and the CSE inhibitor(PPG)significantly reduced H2S levels in the JWDSD group rats(P<0.01).(2)Compared with the normal control group,the myocardial tissue necrosis and cell destruction occurred in the MIRI model group,and JWDSD could alleviate the myocardial tissue necrosis of model rats,but the ameliorative effect of JWDSD could be reversed by PPG.(3)Beclin1,LC3 A/B,and p62 expression levels in the heart tissues of the model group were significantly increased(P<0.001),whereas decreased by JWDSD(P<0.05,P<0.01,and P<0.001,respectively),and the inhibitory effects of JWDSD on Beclin1,LC3 A/B,and p62 expression were partially reversed by PPG(P<0.01,P<0.05,and P<0.01,respectively).(4)The expression levels of autophagy-related genes Beclin1 and ATG5 were significantly increased in the model group(P<0.001).JWDSD clearly downregulated the expression levels of Beclin1 and ATG5(P<0.05 and P<0.001,respectively),which were reversed by PPG(P<0.001).Conclusion Our experimental data show that JWDSD can exhibit an anti-MIRI role by increasing endogenous H2S generation,and downregulating the expression of Beclin1,LC3 A/B,p62 and ATG5,which are related to inhibiting autophagy signaling.
文摘This study examined the protective effect of ischemic postconditioning(IPoC) and minocycline postconditioning(MT) on myocardial ischemia-reperfusion(I/R) injury in atherosclerosis(AS) animals and the possible mechanism.Forty male healthy rabbits were injected with bovine serum albumin following feeding on a high fat diet for 6 weeks to establish AS model.AS rabbits were randomly divided into 3 groups:(1) I/R group,the rabbits were subjected to myocardial ischemia for 35 min and then reperfusion for 12 h;(2) IPoC group,the myocardial ischemia lasted for 35 min,and then reperfusion for 20 s and ischemia for 20 s [a total of 3 cycles(R20s/I20s×3)],and then reperfusion was sustained for 12 h;(3) MT group,minocycline was intravenously injected 10 min before reperfusion.The blood lipids,malondialdehyde(MDA),superoxide dismutase(SOD),soluble cell adhesion molecule(sICAM),myeloperoxidase(MPO),and cardiac troponin T(cTnT) were biochemically determined.The myocardial infarction size(IS) and apoptosis index(AI) were measured by pathological examination.The expression of bcl-2 and caspase-3 was detected in the myocardial tissue by using reverse transcription-polymerase chain reaction(RT-PCR).The results showed that the AS models were successfully established.The myocardial IS,the plasma levels of MDA,sICAM,MPO and cTnT,and the enzymatic activity of MPO were significantly decreased,and the plasma SOD activity was significantly increased in IPoC group and MT group as compared with I/R group(P<0.05 for all).The myocardial AI and the caspase-3 mRNA expression were lower and the bcl-2 mRNA expression was higher in IPoC and MT groups than those in I/R group(all P<0.05).It is concluded that the IPoC and MT can effectively reduce the I/R injury in the AS rabbits,and the mechanisms involved anti-oxidation,anti-inflammation,up-regulation of bcl-2 expression and down-regulation of caspase-3 expression.Minocycline can be used as an effective pharmacologic postconditioning drug to protect myocardia from I/R injury.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82070367).
文摘To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending(LAD)coronary artery,we first randomly divided 16 male Bama pigs into a sham group and a model group.After anesthesia,we separated the arteries and veins.Subsequently,we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision.Then,we loosened and released the ligation line after five minutes of pre-occlusion.Finally,we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia.Compared with the sham group,electrocardiogram showed multiple continuous lead ST-segment elevations,and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group.Twenty-four hours after the operation,cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group,compared with the sham group.Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group.Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group.All eight pigs in the model group recovered with normal sinus heart rates,and the survival rate was 100%.In conclusion,the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.
基金supported fiancially by the Natural Science Foundation of Inner Mongolia Autonomous Region in China(Grant No.2018MS08043)Inner Mongolia Autonomous Region Scientific and Technological Achievements Transformation Guidance Project in China(2020PT0030).
文摘Background:Ischemia-reperfusion can worsen myocardial damage and increase the risk of death.Studies have revealed that ischemic preconditioning provides the best endogenous protection against myocardial ischemia-reperfusion injury(MIRI),and the principle of electroacupuncture(EA)preconditioning is comparable to that of myocardial ischemic preconditioning adaption.Our earlier research demonstrated that EA pretreatment inhibits the expression of calmodulin-dependent protein kinase IIδ(CaMKIIδ),sodium/calcium exchanger 1(NCX1),and cyclophilin D,hence providing protection against MIRI.However,the exact mechanism is still unknown.The expression of NCX1 mRNA is directly regulated by microRNA-214(miR-214).Moreover,it suppresses the levels of CaMKIIδand cyclophilin D.Whether these variables contribute to EA preconditioning to improve MIRI needs to be investigated,though.This study aimed to preliminarily determine whether EA pretreatment ameliorates MIRI by modulating the miR-214-3p/NCX1 axis.Methods:We used a rat MIRI model to investigate the effect of EA pretreatment on MIRI and the expression of miR-214-3p.In addition,adenovirus injection inhibited miR-214-3p expression in the rat MIRI model,and the influence of EA pretreatment towards MIRI was observed in the context of blocked miR-214-3p expression.Both the myocardial histological abnormalities and the alterations in the ST segment of the rat electrocardiogram were analyzed.NCX1 mRNA,cyclophilin D,and CaMKIIδexpression levels were also analyzed.Results:EA pretreatment improved MIRI.In rats with MIRI,EA administration increased miR-214-3p expression while decreasing NCX1 mRNA,cyclophilin D,and CaMKIIδproteins in cardiac tissues.The beneficial effect of EA pretreatment against MIRI was reversed,coupled with elevated levels of NCX1 mRNA,cyclophilin D,and CaMKIIδprotein expression,when an adenovirus injection disrupted the expression of miR-214-3p.Conclusions:Our findings preliminarily show that EA pretreatment inhibits the expression of NCX1 mRNA,cyclophilin D,and CaMKIIδproteins via miR-214-3p,hence exerting MIRI protection.
基金supported by National Natural Science Foundation of China(No.81670334/No.81800262)Science and Technology Planning Project of Guangzhou(No.201903010005)+1 种基金Science and Technology Planning Project of Guangzhou(No.201906010089)Natural Science Foundation of Guangdong Province(No.2018A030313029)
文摘Background Myocardial ischemia/reperfusion(I/R)injury remains a great challenge in clinical therapy.Recent studies indicated that circularRNA(circRNA)play an important role in the regulation of atherosclerotic heart disease.However,as a new circRNA,the effect of circRNA regulating ischemia-reperfusion through microRNA-1(CRIRTM)on myocardial apoptosis during myocardial ischemia/reperfusion is still unknown.The purpose of this study was to investigate the effect of CRIRTM on I/R-induced apoptosis and the expression of microRNA-1(miR-1)and calmodulin(CaM)in cultured neonatal rat ventricular cardiomyocytes(NRVCs)in vitro and SD rat hypoxia-reoxygenation model in vivo.Methods NRVCs were subjected to hypoxia for 30 minutes and then oxygen was added for 12 hours to establish the model of cell ischemia reperfusion.The SD rats were subjected to the surgery of ligating the anterior descending branch of the left coronary artery for 4 hours and then reperfused for 48 hours to establish myocardial ischemia animal model.The expression of CRIRTM,miIR-1 and CaM was detected by quantitative real-time polymerase chain reaction(qRT-PCR).TUNEL was used to analyze the apoptosis level of cells and animal myocardium after small interfering RNA(siRNA)down-regulation of CRIRTM.The expression of CRIRTM in the blood of patients with myocardial infarction was detected,and the downstream of CRIRTM was analyzed by Target Scan.Results The specific upregulation of CRIRTM was detected in the plasma of patients with ST-segment elevation myocardial infarction after reperfusion,and multiple binding sites between CRIRTM and miR-1 were found by Target Scan analysis.The expression of CRIRTM and CaM was up-regulated and the expression of miR-1 was down-regulated in cells and rats I/R model.Both in vivo and in vitro,cardiomyocyte apoptosis induced by myocardial ischemia-reperfusion will increase after down-regulation of CRIRTM.It may be due to the decreased inhibition of miR-1 by down-regulated CRIRTM,which increases the degradation of CaM by miR-1 and aggravates cardiomyocyte apoptosis.Conclusions Our data demonstrated that CRIRTM alleviates myocardial ischemia-reperfusion injury via suppressing miR-1 leading to enhanced CaM levels.[S Chin J Cardiol 2021;22(1):30-37]
基金Supported by the National Natural Science Foundation of China,No.82200270.
文摘BACKGROUND Myocardial ischemia-reperfusion injury(MIRI)poses a prevalent challenge in current reperfusion therapies,with an absence of efficacious interventions to address the underlying causes.AIM To investigate whether the extracellular vesicles(EVs)secreted by adipose mesenchymal stem cells(ADSCs)derived from subcutaneous inguinal adipose tissue(IAT)underγ-aminobutyric acid(GABA)induction(GABA-EVs^(IAT))demonstrate a more pronounced inhibitory effect on mitochondrial oxidative stress and elucidate the underlying mechanisms.METHODS We investigated the potential protective effects of EVs derived from mouse ADSCs pretreated with GABA.We assessed cardiomyocyte injury using terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/propidium iodide assays.The integrity of cardiomyocyte mitochondria morphology was assessed using electron microscopy across various intervention backgrounds.To explore the functional RNA diversity between EVs^(IAT)and GABA-EVs^(IAT),we employed microRNA(miR)sequencing.Through a dual-luciferase reporter assay,we confirmed the molecular mechanism by which EVs mediate thioredoxin-interacting protein(TXNIP).Western blotting and immunofluorescence were conducted to determine how TXNIP is involved in mediation of oxidative stress and mitochondrial dysfunction.RESULTS Our study demonstrates that,under the influence of GABA,ADSCs exhibit an increased capacity to encapsulate a higher abundance of miR-21-5p within EVs.Consequently,this leads to a more pronounced inhibitory effect on mitochondrial oxidative stress compared to EVs from ADSCs without GABA intervention,ultimately resulting in myocardial protection.On a molecular mechanism level,EVs regulate the expression of TXNIP and mitigating excessive oxidative stress in mitochondria during MIRI process to rescue cardiomyocytes.CONCLUSION Administration of GABA leads to the specific loading of miR-21-5p into EVs by ADSCs,thereby regulating the expression of TXNIP.The EVs derived from ADSCs treated with GABA effectively ameliorates mitochondrial oxidative stress and mitigates cardiomyocytes damage in the pathological process of MIRI.
基金Seed Fund of Shanghai Medical College(No.SFP-18-21-14-004).
文摘Objective:To investigate the therapeutic effect of microRNA210(miRNA-210)modified mesenchymal stem cells(MSCs)on myocardial ischemia-reperfusion injury(MIRI)model rats.Methods:One SD rat was sacrificed,and the lower extremity tibia and femur were isolated.MSCs were cultured by whole bone marrow adherence method to construct miRNA-210 modified MSCs.40 SD rats were divided into the sham operation group,model group,MSCs group,and miRNA-210+MSCs group,with 10 rats in each group.The left anterior descending coronary artery was ligated to prepare a model of myocardial ischemia and reperfusion.After successful modeling,50μl of MSCs suspension was injected into the tail vein of the MSCs group,and 50μl of miRNA-210 modified MSCs suspension was injected into the tail vein of the miRNA-210+MSCs group.The sham operation group and the model group were injected with the same amount of normal saline.On the 10th day after modeling,the area of myocardial infarction,morphological changes of myocardial tissue,myocardial cell apoptosis rate,and miRNA-210 expression were compared in each group.Results:The area of myocardial infarction and the rate of myocardial cell apoptosis in the model group were significantly higher than those in the sham operation group(<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the MSCs group were significantly lower than those in the sham operation group(P<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the miRNA-210+MSCs group were significantly higher than those in the MSCs group(P<0.05);The area of myocardial infarction and the rate of myocardial cell apoptosis in the miRNA-210+MSCs group were significantly lower than those in the sham operation group(P<0.05).The expression level of miRNA-210 in the myocardial tissue of the model group was significantly higher than that in the sham operation group(P<0.05);There were no significantly different in the expression level of miRNA-210 in the myocardial tissue between the MSCs group and model group(P>0.05);The expression level of miRNA-210 in the myocardial tissue of MSCs group was significantly higher than in the MSCs group,model group and sham operation group(P<0.05).HE staining showed that the miRNA-210+MSCs group had normal morphology of myocardial tissues,more uniform cytoplasmic staining,and arranged neatly myocardial fibers.The inflammatory cell infiltration and interstitial edema of the miRNA-210+MSCs group were significantly improved compared with the model group and MSCs group.Conclusion:MiRNA-210 modified MSCs can inhibit myocardial cell apoptosis in myocardial ischemia-reperfusion injury model rats,reduce the area of myocardial infarction,and improve pathological damage of myocardial tissue in rats,which has a certain therapeutic effect on myocardial ischemia-reperfusion injury.
基金We acknowledge the teachers from the Institute of Radiation Medicine,Chinese Academy of Medical Sciences for the I/R help in animal experiments。
文摘Background:Currently,no drugs can specifically improve clinical cardiac ischemia-reperfusion injury or the prognosis of hemodialysis.Salvianolic acid B(SalB)is a widely used cardiac protectant;however,its clinical application is limited by its low oral bioavailability and poor intestinal absorption.The exploration of its preparation and clinical applications has become a research hotspot in recent years.Methods:To determine whether mesoporous silica nanoparticles(MSNs)efficiently delivered SalB to the heart and SalB@MSNs-RhB reduced myocardial ischemia-reperfusion injury,we constructed a myocardial ischemia-reperfusion male rat model,hypoxia/reoxygenation cardiomyocytes,and treated them with SalB@MSNs-RhB.Results:SalB@MSNs-RhB showed improved bioavailability,therapeutic effect,heightened JAK2/STAT3-dependent pro-survival signaling,and antioxidant responses,thereby protecting cardiomyocytes from ischemia-reperfusion injury-induced oxidative stress and apoptosis.Conclusion:This use of SalB-loaded nanoparticles and investigation of their mechanism of action may provide a new strategy for treating cardiomyocytes.Thus,hypoxia/reoxygenation promotes the clinical application of SalB.
文摘Purpose: Ischemia-reperfusion (I/R) injury exacerbates myocardial cell death (including apoptosis and necrosis), leading to complications such as arrhythmias, myocardial stenosis, microvascular obstruction and heart failure, and it is particularly important to seek new strategies to mitigate reperfusion injury. In this paper, we will investigate whether atorvastatin can alleviate myocardial ischemia-reperfusion injury and verify its molecular mechanism. Methods: We successfully constructed a hypoxia-reperfusion (H/R) H9c2 cell model and transfected miR-26a-5p mimic, miR-26a-5p inhibitor and its negative control NC-mimic or NC-inhibitor into H9c2 cells using a transfection kit. The expression of miR-26a-5p and FOXO1 were detected by RT-qPCR assay, the expression of related proteins by Western blot assay, the cell viability of H9c2 cells by CCK-8 assay, the apoptosis rate of H9c2 cells by flow cytometry, the CK and LDH activity in cells by CK and LDH assay kits. The targeting relationship between miR-26a-5p and FOXO1 was verified by dual luciferase reporter gene assay. Results: MiR-26a-5p expression was decreased in H/R-induced cells and FOXO1 expression was increased in H/R-induced cells. Atorvastatin alleviated H/R injury in cardiomyocytes and was most effective at a concentration of 1 μM. Atorvastatin alleviated H/R injury in cardiomyocytes by upregulating miR-26a-5p expression, miR-26a-5p and FOXO1 were negatively regulated by targeting. Conclusion: Atorvastatin can alleviate H/R injury in cardiomyocytes by regulating miR-26a-5p/FOXO1.
基金supported by grants from the National Nature Foundation Youth Program(No.82002095)。
文摘Background Myocardial ischemia-reperfusion injury is characterized by the inability of tissue and organ function to recover after the perfusion blood flow is restored followed by myocardial ischemia.Previous studies have shown that many Chinese herbal compounds can reduce myocardial ischemia-reperfusion injury,but the efficacy of Wuling Powder in treating myocardial ischemia-reperfusion injury has not been reported.The present study aimed to investigate the mechanism of Wuling Powder in treating myocardial ischemia-reperfusion injury by network pharmacology and molecular docking.Methods The active constituents of Wuling Powder were obtained by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and the related targets of active constituents of Wuling Powder were screened by the Swiss Target Prediction database.Disease targets of myocardial ischemia-reperfusion injury were obtained by Gene Cards,Dis Ge NET and OMIM gene databases.The active compound-target network of Wuling Powder was constructed using Cytoscape software.The drug prediction targets were mapped to the disease target set,and the intersection targets were obtained.The Gene Ontology(GO)function and Kyoto Encyclopedia of Genes anf Genomes(KEGG)pathway enrichment analysis were performed on the intersection targets obtained by using String database.Auto Dock Vina was used for molecular docking of core targets and the top 3 key active ingredients with degree values.Results Through screening,56 active ingredients and 116 targets of Wuling Powder were obtained.There were 27 common targets of Wuling Powder and myocardial ischemia-reperfusion injury in Myocardial ischemia-reperfusion injury(MIRI).Protein-Protein Interaction(PPI)network analysis in this study showed that CASP3,PTGS2,CAT,JUN,ESR1,CASP8,CASP9 and RELA may be the key targets of Wuling Powder to exert the protective effect of MIRI.GO functional analysis and KEGG pathway enrichment analysis showed that biological processes such as apoptosis,lipopolysaccharide response,steroid hormone response and signal transduction pathways such as PTGS2,TNF-α,nuclear transcription factor-κB(NF-κB),MAPK,PI3K/AKT,NLRP3,and autophagy play an important role in the occurrence and development of MIRI.Molecular docking results showed thatβ-sitosterol and hederagenin had good binding activities with key targets such as PTGS2,CASP3,and CAT.Conclusions Wuling Powder may act on CASP3,PTGS,CAT,JUN,ESR1,CASP8,CASP9 and other targets throughβ-sitosterol,hederagenin,3β-acetoxyatractylone,taxifolin and other active ingredients.[S Chin J Cardiol 2024;25(3):179-192]
文摘Background Myocardial ischemia-reperfusion injury(MI/RI)is an important complication after reperfusion therapy in ischemic cardiomyopathy.Its pathogenesis is complex,and there is no effective prevention and treatment measures.It has been confirmed that apoptosis,ferroptosis,pyroptosis and other different cell death forms are involved in the pathophysiological process of MI/RI.This article reviews the research progress of the above different forms of cell death in MI/RI in recent years,hoping to provide a new reference for the prevention and treatment of MI/RI.
基金supported by the National Natural Science Foundation of China (30701066 and 30973696 Science) for financial support
文摘Objective: To evaluate the myocardial protective effect of Gualou Xiebai Banxia decoction (瓜蒌薤白半夏汤GXBD) and explore the mechanisms of inhibition of NF-kappa B activation and blockade of inflammatory responses induced by ischemia-reperfusion in rats. Methods: Twenty-four Sprague Dawley (SD) rats were randomly divided into three groups. Rats in the treatment group received GXBD (13 g crude drug/kg) for three weeks, while rats in the model control and normal control groups received equal volumes of distilled water. On the 22nd day, rats in the ischemia-reperfusion (I/R) control and GXBD-treated groups underwent 30 min occlusion of the left anterior descending (LAD) coronary artery, followed by 120 min reperfusion. Electrocardiogram was recorded, and the activities of cardiac enzymes, cytokines, and NF-кB were assessed after I/R. Results: Compared with the I/R control group, GXBD treatment restored the activity of the specific myocardial-injury marker creatine kinase (CK) and lactate dehydrogenase (LDH), and inhibited the inflammatory response involving the nuclear factor-кB (NF-кB) pathway, including down-regulation of interleukin (IL)-1β and IL-6, and up-regulation of IL-10 gene expression. Conclusion: GXBD strongly reduced myocardial impairment in our I/R model, including inhibition of NF-кB activation and inflammatory cytokine responses.
文摘Our knowledge and understanding of the pathophysiology of coronary atherosclerosis has increased enormously over the last 20 years.Reperfusion through thrombolysis or percutaneous coronary angioplasty is the standard treatment for preventing acute myocardial infarction.Early reperfusion is an absolute prerequisite for survival of the ischemic myocardium,but reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone.These outcomes,in a range of reperfusion-associated pathologies,are collectively termed "reperfusion injuries".Reactive oxygen species are known to be produced in large quantities in the first few minutes of the post-ischemia reperfusion process.Similarly,scientific evidence from the last 15 years has suggested that melatonin has beneficial effects on the cardiovascular system.The presence of vascular melatoninergic receptor binding sites has been demonstrated;these receptors are functionally linked to vasoconstrictor or vasodilatory effects of melatonin.It has been shown that patients with coronary heart disease have a low melatonin production rate,especially those with higher risk of cardiac infarction and/or sudden death.Melatonin attenuates molecular and cellular damage resulting from cardiac ischemia-reperfusion in which destructive free radicals are involved.
文摘A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion （I/R） injury. This tightly orchestrated cata-bolic cellular‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protec-tive mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the va-riability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin （mTOR） inhibitors, adenosine monophosphate-activated protein kinase （AMPK） modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic ma-nipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.
基金supported by Planning Program of Department of Science and Technology of Liaoning Province(Grant No.2011225015)
文摘To explore mechanism and protective effect of rosiglitazone on myocardial ischemia reperfusion(I/R) injury.Methods:A total of 48 male Japanese white big-ear rabbits were randomly divided into control group(A),I/R group(B),low dose of rosiglitazone group(C),high dose of rosiglitazone group(D).Plasma concentration of and also reduced the concentration of plasma serum creatine kinase(CK),CK-MB.high-sensitivity C-reactive protein(hsCRP).ultrasuperoxide dismutase(SOD),malondialdehyde(MD.A).lactic acid glutathione skin peroxidase (C-SH-PX).nitric oxide(NO)and endothelin(ET) were measured 1 h later after I/R.Twenty-four hours after I/R the hearts were harvested for pathological and ultrastructural analysis.Area of myocardial infarction were tested.Results:Plasma concentration of CK,Ck-MB.hsCRP,NO. MDA and ET were decreased in C,D group compared with group B.Plasma concentration of T-SOD and GSH-Px were increased significantly in C.D group compared with group B.Compared with group B.pathological and ullraslructural changes in C and D group were slightly.There was significant difference in myocardial infarction area between group C.D and group B(P【0.05). Myocardial infarction area and arrhythmia rate were lower in group C,D compare with group B. Rosiglitazone may protect myocardium from I/R injury by enhancing T-SOD and GSH-Px concentration,inhibit inflammatory reaction,and improve endothelial function.
