A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly und...A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly understood.Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction(TAC)and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy(DCM).The results showed that the heart weight to body weight ratio was significantly elevated,and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC.Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle.RNAseq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling,metabolic processes,and signaling cascades associated with pathological cardiomyocyte growth.When combined with ribosome profiling analysis,we revealed that translation efficiency(TE)of 1,495 genes was enhanced,while the TE of 933 genes was inhibited following TAC.In DCM patients,1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level.Although the majority of the genes were not shared between mouse and human,we identified 93 genes,including Nos3,Kcnj8,Adcy4,Itpr1,Fasn,Scd1,etc.,with highly conserved translational regulations.These genes were remarkably associated with myocardial function,signal transduction,and energy metabolism,particularly related to cGMP-PKG signaling and fatty acid metabolism.Motif analysis revealed enriched regulatory elements in the 5′untranslated regions(5′UTRs)of transcripts with differential TE,which exhibited strong cross-species sequence conservation.Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.展开更多
Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarge...Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.展开更多
Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing an...Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing and treating cardiovascular diseases.However,its poor metabolic stability and high permeability across the blood-brain barrier(BBB)make it unsuitable for preventing and treating peripheral cardiovascular diseases.Herein,the hit-to-lead optimization was performed to discover novel 3-trifiuoromethylsubstituted pyrazole derivatives as potent and selective PDE10A inhibitors.The structure-activity relationships,biological characterization,molecular mechanism,and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A(half maximal inhibitory concentration,IC_(50)=11.9 nmol/L),more than 840-fold selectivity over other PDE subtypes,enhanced liver microsomes stability(T_(1/2)=239 min)compared to MP-10 and low BBB permeability.Importantly,oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline(ISO)-induced pathological cardiac hypertrophy in mice,particularly suppressing increase of cardiac weight,atrial natriuretic peptide(ANP)andβ-myosin heavy chain(β-MHC)hypertrophic markers along with cardiac fibrosis.These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.展开更多
Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,med...Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,mediated by secreted proteins,plays a significant role in the development and progression of pathological cardiac hypertrophy.Serpin Family E Member 2(serpinE2),secreted by fibroblasts into the extracellular space,has been implicated in this process.However,whether serpinE2 can be internalized by cardiomyocytes and whether cold exposure influences this process remains unclear.Materials and methods:Mice were subjected to cold exposure(4°C,12 h/day for 8 weeks),and cardiac hypertrophy was induced by transverse aortic constriction(TAC).SerpinE2 expression was silenced by short interfering RNA(siRNA).Cardiac fibroblasts were stimulated with angiotensin II(Ang II)to induce serpinE2 secretion.Exogenous recombinant serpinE2,labeled with DyLight 488 or His-tag,was used to evaluate its internalization and functional role in cardiomyocytes.Internalization was inhibited by using antibodies against serpinE2,heparin,or endocytosis inhibitors(β-cyclodextrin,nystatin,dynasore,and chlorpromazine).Chromatin immunoprecipitation followed by quantitative polymerase chain reaction(PCR)was used to assess the binding of the transcription factor CDX1 to the serpinE2 promoter.Results:Cold exposure significantly increased serpinE2 mRNA and protein expression in mouse hearts.SerpinE2 levels were also upregulated in plasma and cardiac tissue following TAC.Knockdown of serpinE2 attenuated TAC-induced hypertrophy,restored left ventricular function,and reduced atrial natriuretic peptide,brain natriuretic peptide,andβ-myosin heavy chain fragment levels.Exogenous serpinE2 promoted cardiomyocyte hypertrophy,an effect that was reversed by serpinE2 knockdown.Co-culture with conditioned medium from Ang II-stimulated fibroblasts increased serpinE2 expression in cardiomyocytes.Exogenous serpinE2 was internalized via endocytosis,which was inhibited by antibodies,heparin,and endocytosis blockers.Internalized serpinE2 activated the protein kinase B(AKT)/β-catenin pathway in cardiomyocytes.CDX1 bound to the serpinE2 promoter and promoted its transcription in fibroblasts.CDX1 overexpression increased serpinE2 and collagen expression,while its suppression had the opposite effect.Administration of exogenous fibroblast growth factor 4(FGF4)or overexpression of FGF4 plasmid upregulated CDX1,serpinE2,and collagen expression in fibroblasts.Conclusions:SerpinE2 expression is responsive to cold stress and mediates intercellular communication between fibroblasts and cardiomyocytes.Fibroblast-secreted serpinE2 is internalized by cardiomyocytes via endocytosis,promoting hypertrophy through activation of the phosphatidylinositol 3-kinase(PI3K)-AKT/β-catenin pathway.The FGF4-CDX1 axis regulates serpinE2 expression and secretion in cardiac fibroblasts.展开更多
Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skel...Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skeletal muscle. This study aims to examine the relationship between cardiac FNDC5 and aging-related cardiac hypertrophy and decreased skeletal muscle strength. Methods: Male young C57BL/6 mice (5 months old, n = 6) and aged mice (21 months old, n = 6) were utilized in the study and housed in a specific pathogen-free (SPF) environment. Prior to the experiment, grip strength tests were performed on the mice, and heart tissues were collected for morphological analysis, including the assessment of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and fibronectin type III-containing structural domain 5 (FNDC5) protein levels. Furthermore, myosin heavy chain II (MyHC II), skeletal muscle-specific transcription factor (MyoD), muscle RING-finger protein-1 (MuRF1), and FNDC5 levels were evaluated in the quadriceps muscle. The correlations between heart weight and FNDC5 expression levels, as well as skeletal muscle indices in the mice, were subsequently analyzed. Result: Aging leads to cardiac hypertrophy and reduced expression of PGC-1α and FNDC5 proteins. Concurrently, there is a decline in the strength of skeletal muscle, along with decreased expression of MyHC II and increased expression of MURF1 and MyoD. Correlation analysis demonstrated strong positive associations between myocardial FNDC5 protein levels and limb grip strength, as well as MyHC II, and strong negative associations with MyoD and MuRF1. Conclusion: There may be a significant association between aging-induced cardiac hypertrophy and decreased skeletal muscle strength, with FNDC5 potentially playing a crucial role as a regulatory molecule facilitating communication between the heart and skeletal muscle.展开更多
BACKGROUND The existing semi-quantitative ultrasound grading system inadequately evaluates synovial hypertrophy at the dorsal recess of the first metatarsophalangeal joint(MTPJ).Vitamin D deficiency is prevalent in ty...BACKGROUND The existing semi-quantitative ultrasound grading system inadequately evaluates synovial hypertrophy at the dorsal recess of the first metatarsophalangeal joint(MTPJ).Vitamin D deficiency is prevalent in type 2 diabetes mellitus(T2DM)and may influence joint inflammation.This study hypothesizes that serum 25-hydro-xyvitamin D[25(OH)D]levels are inversely associated with synovial hypertrophy severity of the first MTPJ in patients with T2DM.AIM To refine ultrasound grading for the first MTPJ synovial hypertrophy and inves-tigate its association with vitamin D in T2DM.METHODS This cross-sectional study included 56 patients(112 MTPJs)with T2DM from Shenzhen Traditional Chinese Medicine Hospital.Synovial hypertrophy was evaluated using a refined semi-quantitative ultrasound grading system focusing on the dorsal recess overlying the metatarsal bone.Serum 25(OH)D levels were measured.Logistic regression and threshold analyses assessed associations between vitamin D status and hypertrophy severity.RESULTS Of 112 joints assessed,98 exhibited synovial hypertrophy(grade 1:40;grade 2:50;grade 3:8).The refined grading system demonstrated strong intra-and inter-observer reliability(intraclass correlation coefficients=0.79 and 0.73,respectively).Lower serum 25(OH)D(<24.3 ng/mL)was independently associated with moderate-to-severe hypertrophy[odds ratio(OR)=0.83;P=0.0163].Vitamin D deficiency significantly increased the likelihood of moderate-to-severe hypertrophy compared with non-deficiency(OR=3.86;P=0.0422).Threshold analysis identified 23.8 ng/mL as a critical serum 25(OH)D level,below which each increment reduced moderate-to-severe hypertrophy risk by 21%(OR=0.79;P=0.0078).CONCLUSION The refined ultrasound grading system demonstrated strong reliability.Serum 25(OH)D may serve as a protective factor against the severity of synovial hypertrophy in T2DM patients with lower 25(OH)D levels.展开更多
Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was...Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was developed via comprehensive allergic sensitization,chronic inflammation induction,and chronic intermittent hypoxia(CIH).The modeling process involved three steps:female Sprague-Dawley rats(aged 4-5 weeks)were used for modeling.Allergen sensitization was induced via intraperitoneal administra-tion and intranasal provocation using ovalbumin(OVA);chronic nasal inflammation was induced through intranasal lipopolysaccharide(LPS)administration for sustained nasal irritation;CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber.Postmodel establishment,behaviors,and histologi-cal changes in nasopharynx-associated lymphoid tissue(NALT)and nasal mucosa were assessed.Arterial blood gas analysis and quantification of serum and tissue levels of(interleukin)IL-4 and IL-13,OVA-specific immunoglobulin E(sIgE),eosinophil cationic protein(ECP),tumor necrosis factor(TNF-α),IL-17,and transforming growth factor(TGF)-βwere conducted for assessment.The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated.Results:Rats exhibited notable nasal symptoms and hypoxia after modeling.Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa in-flammatory cell infiltration.Elevated IL-4,IL-13,IL-17,OVA-sIgE,ECP,and TNF-αlev-els and reduced TGF-βlevels were observed in the serum and tissue of model-group rats.After a week of treatment,the treatment group exhibited symptom and inflam-matory factor improvement.Conclusion:The model effectively simulates AH symptoms and pathological changes.But it should be further validated for genetic,immunological,and hormonal back-grounds in the currently used and other strains and species.展开更多
BACKGROUND Right ventricular hypertrophy(RVH)occurs because of volume or pressure overload within the right ventricular(RV)system.RVH is associated with complex pathological changes,including myocardial cell injury,ap...BACKGROUND Right ventricular hypertrophy(RVH)occurs because of volume or pressure overload within the right ventricular(RV)system.RVH is associated with complex pathological changes,including myocardial cell injury,apoptosis,myocardial fibrosis,neuroendocrine disturbances,and abnormal water and liquid metabolism.Ferroptosis,a novel type of iron-dependent cell death characterized by lipid peroxide accumulation,is an important mechanism of cardiomyocyte death.However,the role of ferroptosis in RVH has rarely been studied.We hypothesize that hydrogen(H_(2)),an experimental medical gas with superior distri-bution characteristics,inhibits ferroptosis.AIM To explore the protective effect of H_(2) on RVH and the mechanism by which H_(2) regulates ferroptosis.METHODS An in vivo RVH rat model was induced by monocrotaline(MCT)in 30 male Sprague-Dawley rats.An H9C2 cell model was treated with angiotensin II to simulate pressure overload in the RV system in vitro.H_(2) was administered to rats by inhalation(2%for 3 hours daily for 21 days)and added to the cell culture medium.The Nrf2 inhibitor ML385(1μM)was used to investigate anti-ferroptotic mechanisms.RESULTS In MCT-treated rats,H_(2) inhalation decreased RVH;the RV wall thickness decreased from 3.5±0.3 mm to 2.8±0.2 mm(P<0.05)and the RV ejection fraction increased from 45±3%to 52±4%(P<0.05).In H9C2 cells,H_(2) alleviated hypertrophy.H_(2) inhibited ferroptosis by modulating the iron content,oxidative stress,and ferroptosis-related proteins,thereby restoring the Nrf2/HO-1 signaling pathway.CONCLUSION H_(2) retards RVH by inhibiting ferroptosis via Nrf2/HO-1 restoration,suggesting a new treatment strategy.展开更多
Childhood adenotonsillar hypertrophy is associated with complications,including mouth breathing and obstructive sleep apnea hypopnea syndrome(OSAHS),which can lead to sleep-related ventilation problems that significan...Childhood adenotonsillar hypertrophy is associated with complications,including mouth breathing and obstructive sleep apnea hypopnea syndrome(OSAHS),which can lead to sleep-related ventilation problems that significantly impact the development of orofacial myofunctions as well as the physical and mental health of children.Orofacial myofunctional therapy(OMT)is based on the plasticity of neuromuscular systems to retrain the oral and maxillofacial system,effectively improving orofacial morphology,upper airway structure,and other aspects in pediatric patients.OMT is non-invasive and easy to implement,which can be promoted as an adjuvant therapy for children with adenotonsillar hypertrophy.This review mainly discusses the theoretical basis,training methods,and influencing factors of OMT.展开更多
Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(S...Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(Sema3A)is a membrane-associated secreted protein with chemorepulsive properties for axons.However,the role of Sema3A in articular cartilage is still not clear.In the present studies,we investigated the functions of Sema3A in OA development in mice,non-human primates,and patients with OA.Sema3A has a protective effect on cartilage degradation,validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice.We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway.The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A,and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints.Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage,and could be potentially used for OA treatment.展开更多
Mitochondria play an important role in pressure overload-induced cardiac hypertrophy.The present study aimed to investigate the role of mitochondrial transient receptor potential vanilloid 3(TRPV3)in myocardial hypert...Mitochondria play an important role in pressure overload-induced cardiac hypertrophy.The present study aimed to investigate the role of mitochondrial transient receptor potential vanilloid 3(TRPV3)in myocardial hypertrophy.A 0.7 mm diameter U-shaped silver clip was used to clamp the abdominal aorta of Sprague Dawley(SD)rats and establish an animal model of abdominal aortic constriction(AAC).Rat H9C2 myocardial cells were treated with angiotensin II(Ang II)to establish a hypertrophic myocardial cell model,and TRPV3 expression was knocked down using TRPV3 small interfering RNA(siRNA).JC-1 probe was used to detect mitochondrial membrane potential(MMP).DHE probe was used to detect ROS generation.Enzyme activities of mitochondrial respiratory chain complex I and III and ATP production were detected by assay kits.Immunofluorescence staining was used to detect TRPV3 expression in H9C2 cells.Western blot was used to detect the protein expression levels ofβ-myosin heavy chain(β-MHC),mitochondrial TRPV3 and mitochondrial NOX4.The results showed that,in the rat AAC model heart tissue and H9C2 cells treated with Ang II,the protein expression levels ofβ-MHC,mitochondrial TRPV3 and mitochondrial NOX4 were up-regulated,MMP was decreased,ROS generation was increased,mitochondrial respiratory chain complex I and III enzyme activities were decreased,and ATP production was reduced.After knocking down mitochondrial TRPV3 in H9C2 cells,the protein expression levels ofβ-MHC and mitochondrial NOX4 were down-regulated,MMP was increased,ROS generation was decreased,mitochondrial respiratory chain complex I and III enzyme activities were increased,and ATP production was increased.These results suggest that mitochondrial TRPV3 in cardiomyocytes exacerbates mitochondrial dysfunction by up-regulating NOX4,thereby participating in the process of pressure overload-induced myocardial hypertrophy.展开更多
Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and...Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.展开更多
Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overlo...Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction(AAC).Myocardial hypertrophy was evaluated by measuring the heart weight index(HW/BW),lung weight index(LW/BW),ratio of heart weight to tibia length(HW/TL),ratio of lung weight to tibia length(LW/TL),and cross-sectional area of myocardial cells.qRT-PCR was used to detect the mRNA expression of TRPV4.Western blotting was used to detect the protein expression of TRPV4,mast cell tryptase,myosin heavy chain beta(β-MHC),calcineurin A(CnA),and nuclear factor of activated T-cell c3(NFATc3).ELISA was used to measure the levels of brain natriuretic peptide(BNP)and histamine.Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.Results:Compared with those of the sham rats,the myocardial mast cells,tryptase,HW/BW,LW/BW,HW/TL,and LW/TL,the cross-sectional area of the myocardial cells,and the expression ofβ-MHC,TRPV4,CnA,and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly,whereas the MC stabilizer cromolyn sodium(CS)reversed these indicators.In H9c2 cardiomyocytes,treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4,β-MHC,BNP,CnA and NFATc3 and increased calcium ion influx,whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.Conclusion:Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine,and the Ca^(2+)/CnA/NFATc3 signaling pathway is involved in this process.展开更多
Objective To study the neuroendocrine mechanisms of electroacupuncture （EA） at ＂Neiguan＂ （内关 PC 6） for preventing and treating myocardial hypertrophy. Methods Thirty 3-month-old Sprague-Dawley rats were random...Objective To study the neuroendocrine mechanisms of electroacupuncture （EA） at ＂Neiguan＂ （内关 PC 6） for preventing and treating myocardial hypertrophy. Methods Thirty 3-month-old Sprague-Dawley rats were randomly divided into a normal group, a model group and an EA group according to the random digit table, 10 in each group. Isoprenaline Hydrochloride （ISO） injection was subcutaneously injected to establish the model. EA at ＂Neiguan＂ （内关 PC 6） was applied for rats in the EA group, 20 min each time, once daily, for 14 successive days. No treatment was given to rats in the normal group and the observed. The plasma catecholamine neurotransmitters levels and c determined with high performance liquid chromatography model group. The electrocardiogram （ECG） was hanges of their metabolic products contents were （HLPC） method. Results Compared with the normal group, catecholamine neurotransmitters, such as epinephrin （E）, norepinephrine （NE）, and dopamine （DA） and metabolic products, such as 3-methoxy-4-hydroxyphenylglycol （MHPG）, homovanillic acid （HVA）, and 3,4-dihydroxy-phenyl acetic acid （DOPAC） were significantly increased in the model group （all P〈0.05）. These parameters decreased in the EA group when compared with the model group （all P〈0.05）. Conclusion EA at ＂Neiguan＂ （内关 PC 6） could improve the myocardial hypertrophy, which might be correlated with the neuroendocrine system.展开更多
OBJECTIVE: To investigate the effects of electroacupuncture(EA) at Taichong(LR 3) and Baihui(DU 20)on myocardial hypertrophy in spontaneously hypertensive rats(SHRs).METHODS: Thirty-six SHRs were randomly assigned to ...OBJECTIVE: To investigate the effects of electroacupuncture(EA) at Taichong(LR 3) and Baihui(DU 20)on myocardial hypertrophy in spontaneously hypertensive rats(SHRs).METHODS: Thirty-six SHRs were randomly assigned to model, EA, and Losartan groups, with twelve rats per group. Twelve Wistar Kyoto rats were selected as the normal control group. Systolic blood pressure(SBP) and cardiac function were measured in all rats.Expression levels of factors associated with the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR) pathway were evaluated by Western blotting and real-time PCR.Pathological changes of the heart tissue were observed by hematoxylin-eosin staining.RESULTS: After treatment, enhanced SBP was significantly decreased in the EA and Losartan groups compared with the model group(P < 0.01). Echocardiographic and morphological analyses revealed that enhanced end-diastolic interventricular septal thickness and left ventricular posterior wall thickness, as well as ratio of left ventricular weight to body weight were markedly diminished in the EA and Losartan groups(P < 0.01 or P < 0.05), while reduced left ventricular end-diastolic dimension and left ventricular ejection fraction were significantly ameliorated(P < 0.01). Real-time PCR and western blotting analyses showed that the expression levels of PI3K,Akt, and mT OR in SHRs were significantly up-regulated by EA and Losartan(P < 0.01), while the expression levels of PTEN and ANP were down-regulated(P < 0.01).CONCLUSION: EA at Taichong(LR 3) and Baihui(DU20) inhibited the development of cardiac hypertrophy and improved the cardiac function in SHRs, possibly through regulation of the PI3K/Akt/mTOR signalling pathway.展开更多
Objective： To explore the effect and mechanism of matrine （Mt.） on myocardial interstitial fibrosis induced by pressure overload. Methods： Pressure overloaded myocardial hypertrophy was produced by banding of aort...Objective： To explore the effect and mechanism of matrine （Mt.） on myocardial interstitial fibrosis induced by pressure overload. Methods： Pressure overloaded myocardial hypertrophy was produced by banding of aorta abdominalis in 67 male Sprague-Dawley rats weighing （200±15） g. The rats were assigned into one of the following groups： sham-operation control, operation control, operation group treated with matrine （15 mg/（kg·d）） and treated with carvedilol （Car.） （3.6 mg/（kg·d）） group. The rats were given drugs one day after operation. Five weeks after treatment, the left ventricular weight （LVW） was measured and the volume of myocardial cells was detected with Hematoxylin-Eosin （H-E） stain and Masson stain was used to assess the level of fibrosis of the myocardial matrix. Myocardial metalloproteinase activity was quantified with zymography, and survival rate was calculated. Results： Survival rate significantly decreased （P〈0.05）, LVW/BW （body weight）, MMP-2 （matrix metalloproteinase-2） activity （P〈0.05）, size of cardiomyocytes and interstitial fibrosis obviously increased in the operation group compared with sham control group. Mr. and Car. treatment can significantly increase survival rate （P〈0.05）, decrease LVW/BW （P〈0.05） and MMP-2 activity （P〈0.05）, decrease size of cardiomyocytes and interstitial fibrosis compared with operation group. But there was difference compared with sham group. Conclusion： Matrine was shown to be able to prevent cardiac remodelling of bypertrophy cardium induced by pressure overload including myocardial hypertrophy and fibrosis which may be associated with the decrease in MMP-2 activity of heart.展开更多
During chronic kidney disease (CKD),alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality.The osteoc...During chronic kidney disease (CKD),alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality.The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization,but its effects in CKD are unknown.We tested the hypothesis that DMP1 supplementation in CKD would improve bone health,prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes.We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3^-/- mouse model of CKD.Col4a3^-/- mice demonstrated impaired kidney function,reduced bone DMP1 expression,reduced bone mass,altered osteocyte morphology and connectivity,increased osteocyte apoptosis,increased serum FGF23,hyperphosphatemia,left ventricular hypertrophy (LVH),and reduced survival.Genetic or pharmacological supplementation of DMP1 in Col4a3^-/- mice prevented osteocyte apoptosis,preserved osteocyte networks,corrected bone mass,partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription,and further increased serum phosphate.Despite impaired kidney function and worsened hyperphosphatemia,DMP1 prevented development of LVH and improved Col4a3^-/- survival.Our data suggest that CKD reduces DMP1 expression,whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.展开更多
Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic retic...Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods： Forty male adult Sprague Dawley rats were divided into 5 groups One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1： sham group, rats （n=8） were gavaged with normal saline 2 ml/（kg·d） （ig）; Group 2： control group, rats （n=8） were treated with normal saline 2 ml/（kg·d） （ig）; Group 3： rats （n=8） were given perindopril 2 mg/（kg·d） （ig）; Group 4： rats （n=8） were treated with irbesartan 20 mg/（kg·d） （ig）; Group 5： rats （n=8） were given irbesartan 20 mg/（kg·d） plus perindopril 2 mg/（kg·d） （ig）. Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results： Left ventricular mass index （LVMI）, transverse diameter of myocardial cell （TDM）, calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca^2＋-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca^2＋-ATPase. Conclusion： These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca^2＋-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.展开更多
The changes of proto-oncogene c-fos and c-jun mRNA expression in angiotensin Ⅱ （AngⅡ）-induced hypertrophy and effects of sodium tanshinone ⅡA sulfonate （STS） in the primary culture of neonatal rat cardiomyocyte...The changes of proto-oncogene c-fos and c-jun mRNA expression in angiotensin Ⅱ （AngⅡ）-induced hypertrophy and effects of sodium tanshinone ⅡA sulfonate （STS） in the primary culture of neonatal rat cardiomyocytes were investigated. Twelve neonatal clean grade Wistar rats were selected. The cardiomyocytes were isolated, cultured and divided according to different treatments in the medium. The cardiomyocyte size was determined by phase contrast microscope, and the rate of protein synthesis was measured by [3H]-Leucine incorporation. The c-fos and c-jun mRNA expression in cardiomyocytes was detected by reverse transcription polymerase chain reaction （RT-PCR）. It was found after cardiomyocytes were treated with AngⅡ for 30 min, the c-fos and c-jun mRNA expression in cardiomyocytes was increased significantly （P〈0.01）. After treatment with AngⅡ for 24 h, the rate of protein synthesis in AngⅡ group was significantly increased as compared with control group （P〈0.01）. After treatment with AngⅡ for 7 days, the size of cardiomyocytes in AngⅡ group was increased obviously as compared with control group （P〈0.05）. After pretreatment with STS or Valsartan before AngⅡ treatment, both of them could inhibit the above effects of AngⅡ （P〈0.05 or P〈0.01）. It was suggested that STS could ameliorate AngⅡ-induced cardiomyocyte hy- pertrophy by inhibiting c-fos and c-jun mRNA expression and reducing protein synthesis rate of cardiomyocytes.展开更多
RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling c...RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.展开更多
基金supported by grants from National Natural Science Foundation of China(No.82370392)Shenzhen Medical Research Fund(No.B2302026)+4 种基金Science,Technology and Innovation Commission of Shenzhen Municipality(No.RCJC20210706091947009)National Key R&D Program of China(No.2022YFA1104500)CAMS Innovation Fund for Medical Sciences(No.2023-I2M-1-003 and 2022-I2M-2-001)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT320026)National High Level Hospital Clinical Research Funding(No.2022-GSP-GG-7)。
文摘A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly understood.Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction(TAC)and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy(DCM).The results showed that the heart weight to body weight ratio was significantly elevated,and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC.Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle.RNAseq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling,metabolic processes,and signaling cascades associated with pathological cardiomyocyte growth.When combined with ribosome profiling analysis,we revealed that translation efficiency(TE)of 1,495 genes was enhanced,while the TE of 933 genes was inhibited following TAC.In DCM patients,1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level.Although the majority of the genes were not shared between mouse and human,we identified 93 genes,including Nos3,Kcnj8,Adcy4,Itpr1,Fasn,Scd1,etc.,with highly conserved translational regulations.These genes were remarkably associated with myocardial function,signal transduction,and energy metabolism,particularly related to cGMP-PKG signaling and fatty acid metabolism.Motif analysis revealed enriched regulatory elements in the 5′untranslated regions(5′UTRs)of transcripts with differential TE,which exhibited strong cross-species sequence conservation.Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
文摘Pathological cardiac hypertrophy is an early and significant cardiac structural characteristic that contributes to the onset and progression of heart failure(HF).Its mainly structural feature is the abnormally enlarged cardiomyocyte.Effective intervention targets for abnormally enlarged cardiomyocyte remain to be identified.Previous studies have shown that the cellular shape and size can be regulated by the actin related protein 2/3(Arp2/3)complex,which is an actin-binding protein complex involved in the actin nucleation and assembly.However,the roles of the Arp2/3 complex in cardiomyocyte hypertrophy remain unknown.Here our study identifies its novel roles in the occurrence and development of cardiomyocyte hypertrophy.We found that mRNA levels of all subunits from the Arp2/3 complex are significantly upregulated(P<0.05)in the angiotensin Ⅱ(Ang Ⅱ)-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy.Further studies showed that siRNA-directed ARPC 2 silencing inhibits the reactivation of fetal genes and enlargement of cardiomyocyte area induced by Ang Ⅱ in neonatal rat primary cardiomyocytes(NRCMs)and H9c2 cells(P<0.05).In addition,the upstream activators of the Arp2/3 complex including SH3 protein interacting with Nck,90 kD(SPIN90)and Ras-related C3 botulinum toxin substrate 1(Rac1)/WASp family Verprolin-homologous protein-2(WAVE-2)are upregulated(P<0.05)in Ang Ⅱ-induced neonatal rat primary and H9c2 cardiomyocyte hypertrophy,indicating the excessive activation of the Arp2/3 complex.We further show that CK666,a specific Arp2/3 complex inhibitor,prevents the reactivation of fetal genes and the enlargement of cardiomyocyte area induced by Ang Ⅱ in NRCMs and H9c2 cells(P<0.05).Our results reveal that the Arp2/3 complex plays a crucial role in Ang Ⅱ-induced cardiomyocyte hypertrophy,which is beneficial to further studies about the molecular mechanisms by which the Arp2/3 complex regulates pathological cardiac hypertrophy.
基金supported by the National Natural Science Foundation of China(Nos.22277154,82003576,82273856,22277019,22077143,22377023,82273925)Natural Science Foundation of Guangdong Province(No.2021A1515012499)+1 种基金Fundamental Research Funds for Hainan University(Nos.KYQD(ZR)-21031,KYQD(ZR)-21108,KYQD(ZR)-23003,XTCX2022JKA01)Natural Science Foundation of Hainan Province(Nos.KJRC2023B10,822MS051,824YXQN420,324MS018)。
文摘Recently,MP-10,a previous drug candidate with potent inhibition of phosphodiesterase 10A(PDE10A)in clinical phase II trials for schizophrenia or Alzheimer's disease,has shown significant potential in preventing and treating cardiovascular diseases.However,its poor metabolic stability and high permeability across the blood-brain barrier(BBB)make it unsuitable for preventing and treating peripheral cardiovascular diseases.Herein,the hit-to-lead optimization was performed to discover novel 3-trifiuoromethylsubstituted pyrazole derivatives as potent and selective PDE10A inhibitors.The structure-activity relationships,biological characterization,molecular mechanism,and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A(half maximal inhibitory concentration,IC_(50)=11.9 nmol/L),more than 840-fold selectivity over other PDE subtypes,enhanced liver microsomes stability(T_(1/2)=239 min)compared to MP-10 and low BBB permeability.Importantly,oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline(ISO)-induced pathological cardiac hypertrophy in mice,particularly suppressing increase of cardiac weight,atrial natriuretic peptide(ANP)andβ-myosin heavy chain(β-MHC)hypertrophic markers along with cardiac fibrosis.These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.
基金supported by the National Natural Science Foundation of China(82370279,82170299,82330011,82003757).
文摘Background:Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases,especially in cold environments.The communication between cardiomyocytes and fibroblasts,mediated by secreted proteins,plays a significant role in the development and progression of pathological cardiac hypertrophy.Serpin Family E Member 2(serpinE2),secreted by fibroblasts into the extracellular space,has been implicated in this process.However,whether serpinE2 can be internalized by cardiomyocytes and whether cold exposure influences this process remains unclear.Materials and methods:Mice were subjected to cold exposure(4°C,12 h/day for 8 weeks),and cardiac hypertrophy was induced by transverse aortic constriction(TAC).SerpinE2 expression was silenced by short interfering RNA(siRNA).Cardiac fibroblasts were stimulated with angiotensin II(Ang II)to induce serpinE2 secretion.Exogenous recombinant serpinE2,labeled with DyLight 488 or His-tag,was used to evaluate its internalization and functional role in cardiomyocytes.Internalization was inhibited by using antibodies against serpinE2,heparin,or endocytosis inhibitors(β-cyclodextrin,nystatin,dynasore,and chlorpromazine).Chromatin immunoprecipitation followed by quantitative polymerase chain reaction(PCR)was used to assess the binding of the transcription factor CDX1 to the serpinE2 promoter.Results:Cold exposure significantly increased serpinE2 mRNA and protein expression in mouse hearts.SerpinE2 levels were also upregulated in plasma and cardiac tissue following TAC.Knockdown of serpinE2 attenuated TAC-induced hypertrophy,restored left ventricular function,and reduced atrial natriuretic peptide,brain natriuretic peptide,andβ-myosin heavy chain fragment levels.Exogenous serpinE2 promoted cardiomyocyte hypertrophy,an effect that was reversed by serpinE2 knockdown.Co-culture with conditioned medium from Ang II-stimulated fibroblasts increased serpinE2 expression in cardiomyocytes.Exogenous serpinE2 was internalized via endocytosis,which was inhibited by antibodies,heparin,and endocytosis blockers.Internalized serpinE2 activated the protein kinase B(AKT)/β-catenin pathway in cardiomyocytes.CDX1 bound to the serpinE2 promoter and promoted its transcription in fibroblasts.CDX1 overexpression increased serpinE2 and collagen expression,while its suppression had the opposite effect.Administration of exogenous fibroblast growth factor 4(FGF4)or overexpression of FGF4 plasmid upregulated CDX1,serpinE2,and collagen expression in fibroblasts.Conclusions:SerpinE2 expression is responsive to cold stress and mediates intercellular communication between fibroblasts and cardiomyocytes.Fibroblast-secreted serpinE2 is internalized by cardiomyocytes via endocytosis,promoting hypertrophy through activation of the phosphatidylinositol 3-kinase(PI3K)-AKT/β-catenin pathway.The FGF4-CDX1 axis regulates serpinE2 expression and secretion in cardiac fibroblasts.
文摘Background: Aging-induced cardiac hypertrophy and reduced skeletal muscle strength contribute to increased disease risk and life burden in the elderly. FNDC5 acts as a protective muscle factor in both cardiac and skeletal muscle. This study aims to examine the relationship between cardiac FNDC5 and aging-related cardiac hypertrophy and decreased skeletal muscle strength. Methods: Male young C57BL/6 mice (5 months old, n = 6) and aged mice (21 months old, n = 6) were utilized in the study and housed in a specific pathogen-free (SPF) environment. Prior to the experiment, grip strength tests were performed on the mice, and heart tissues were collected for morphological analysis, including the assessment of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and fibronectin type III-containing structural domain 5 (FNDC5) protein levels. Furthermore, myosin heavy chain II (MyHC II), skeletal muscle-specific transcription factor (MyoD), muscle RING-finger protein-1 (MuRF1), and FNDC5 levels were evaluated in the quadriceps muscle. The correlations between heart weight and FNDC5 expression levels, as well as skeletal muscle indices in the mice, were subsequently analyzed. Result: Aging leads to cardiac hypertrophy and reduced expression of PGC-1α and FNDC5 proteins. Concurrently, there is a decline in the strength of skeletal muscle, along with decreased expression of MyHC II and increased expression of MURF1 and MyoD. Correlation analysis demonstrated strong positive associations between myocardial FNDC5 protein levels and limb grip strength, as well as MyHC II, and strong negative associations with MyoD and MuRF1. Conclusion: There may be a significant association between aging-induced cardiac hypertrophy and decreased skeletal muscle strength, with FNDC5 potentially playing a crucial role as a regulatory molecule facilitating communication between the heart and skeletal muscle.
文摘BACKGROUND The existing semi-quantitative ultrasound grading system inadequately evaluates synovial hypertrophy at the dorsal recess of the first metatarsophalangeal joint(MTPJ).Vitamin D deficiency is prevalent in type 2 diabetes mellitus(T2DM)and may influence joint inflammation.This study hypothesizes that serum 25-hydro-xyvitamin D[25(OH)D]levels are inversely associated with synovial hypertrophy severity of the first MTPJ in patients with T2DM.AIM To refine ultrasound grading for the first MTPJ synovial hypertrophy and inves-tigate its association with vitamin D in T2DM.METHODS This cross-sectional study included 56 patients(112 MTPJs)with T2DM from Shenzhen Traditional Chinese Medicine Hospital.Synovial hypertrophy was evaluated using a refined semi-quantitative ultrasound grading system focusing on the dorsal recess overlying the metatarsal bone.Serum 25(OH)D levels were measured.Logistic regression and threshold analyses assessed associations between vitamin D status and hypertrophy severity.RESULTS Of 112 joints assessed,98 exhibited synovial hypertrophy(grade 1:40;grade 2:50;grade 3:8).The refined grading system demonstrated strong intra-and inter-observer reliability(intraclass correlation coefficients=0.79 and 0.73,respectively).Lower serum 25(OH)D(<24.3 ng/mL)was independently associated with moderate-to-severe hypertrophy[odds ratio(OR)=0.83;P=0.0163].Vitamin D deficiency significantly increased the likelihood of moderate-to-severe hypertrophy compared with non-deficiency(OR=3.86;P=0.0422).Threshold analysis identified 23.8 ng/mL as a critical serum 25(OH)D level,below which each increment reduced moderate-to-severe hypertrophy risk by 21%(OR=0.79;P=0.0078).CONCLUSION The refined ultrasound grading system demonstrated strong reliability.Serum 25(OH)D may serve as a protective factor against the severity of synovial hypertrophy in T2DM patients with lower 25(OH)D levels.
基金This work was financially supported by the National Natural Science Foundation of China(grant number:8217150152)the Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(grant number:SHDC12021102)the Shanghai Three-Year Action Plan to Further Accelerate the Development of Traditional Chinese Medicine Inheritance and Innovation(grant number:ZY(2021-2023)-0209-05).
文摘Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was developed via comprehensive allergic sensitization,chronic inflammation induction,and chronic intermittent hypoxia(CIH).The modeling process involved three steps:female Sprague-Dawley rats(aged 4-5 weeks)were used for modeling.Allergen sensitization was induced via intraperitoneal administra-tion and intranasal provocation using ovalbumin(OVA);chronic nasal inflammation was induced through intranasal lipopolysaccharide(LPS)administration for sustained nasal irritation;CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber.Postmodel establishment,behaviors,and histologi-cal changes in nasopharynx-associated lymphoid tissue(NALT)and nasal mucosa were assessed.Arterial blood gas analysis and quantification of serum and tissue levels of(interleukin)IL-4 and IL-13,OVA-specific immunoglobulin E(sIgE),eosinophil cationic protein(ECP),tumor necrosis factor(TNF-α),IL-17,and transforming growth factor(TGF)-βwere conducted for assessment.The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated.Results:Rats exhibited notable nasal symptoms and hypoxia after modeling.Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa in-flammatory cell infiltration.Elevated IL-4,IL-13,IL-17,OVA-sIgE,ECP,and TNF-αlev-els and reduced TGF-βlevels were observed in the serum and tissue of model-group rats.After a week of treatment,the treatment group exhibited symptom and inflam-matory factor improvement.Conclusion:The model effectively simulates AH symptoms and pathological changes.But it should be further validated for genetic,immunological,and hormonal back-grounds in the currently used and other strains and species.
文摘BACKGROUND Right ventricular hypertrophy(RVH)occurs because of volume or pressure overload within the right ventricular(RV)system.RVH is associated with complex pathological changes,including myocardial cell injury,apoptosis,myocardial fibrosis,neuroendocrine disturbances,and abnormal water and liquid metabolism.Ferroptosis,a novel type of iron-dependent cell death characterized by lipid peroxide accumulation,is an important mechanism of cardiomyocyte death.However,the role of ferroptosis in RVH has rarely been studied.We hypothesize that hydrogen(H_(2)),an experimental medical gas with superior distri-bution characteristics,inhibits ferroptosis.AIM To explore the protective effect of H_(2) on RVH and the mechanism by which H_(2) regulates ferroptosis.METHODS An in vivo RVH rat model was induced by monocrotaline(MCT)in 30 male Sprague-Dawley rats.An H9C2 cell model was treated with angiotensin II to simulate pressure overload in the RV system in vitro.H_(2) was administered to rats by inhalation(2%for 3 hours daily for 21 days)and added to the cell culture medium.The Nrf2 inhibitor ML385(1μM)was used to investigate anti-ferroptotic mechanisms.RESULTS In MCT-treated rats,H_(2) inhalation decreased RVH;the RV wall thickness decreased from 3.5±0.3 mm to 2.8±0.2 mm(P<0.05)and the RV ejection fraction increased from 45±3%to 52±4%(P<0.05).In H9C2 cells,H_(2) alleviated hypertrophy.H_(2) inhibited ferroptosis by modulating the iron content,oxidative stress,and ferroptosis-related proteins,thereby restoring the Nrf2/HO-1 signaling pathway.CONCLUSION H_(2) retards RVH by inhibiting ferroptosis via Nrf2/HO-1 restoration,suggesting a new treatment strategy.
文摘Childhood adenotonsillar hypertrophy is associated with complications,including mouth breathing and obstructive sleep apnea hypopnea syndrome(OSAHS),which can lead to sleep-related ventilation problems that significantly impact the development of orofacial myofunctions as well as the physical and mental health of children.Orofacial myofunctional therapy(OMT)is based on the plasticity of neuromuscular systems to retrain the oral and maxillofacial system,effectively improving orofacial morphology,upper airway structure,and other aspects in pediatric patients.OMT is non-invasive and easy to implement,which can be promoted as an adjuvant therapy for children with adenotonsillar hypertrophy.This review mainly discusses the theoretical basis,training methods,and influencing factors of OMT.
基金partly National Key R&D Program of China(2023YFA1801200,2023YFA1801202)Major Program of the National Natural Science Foundation of China(T2394532)+6 种基金National Natural Science Foundation of China(82072489)The Foundation of Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019007)Shenzhen Medical Research Fund(B2302011)The Sanming Project of Medicine in Shenzhen(SZZYSM202311013)The China Postdoctoral Science Foundational,2023M743679Shenzhen Science and Technology Research Funding(JCYJ20220818101414032)Key Research Project of Science&Technology Department of Sichuan Province,China(2024YFFK0041)。
文摘Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(Sema3A)is a membrane-associated secreted protein with chemorepulsive properties for axons.However,the role of Sema3A in articular cartilage is still not clear.In the present studies,we investigated the functions of Sema3A in OA development in mice,non-human primates,and patients with OA.Sema3A has a protective effect on cartilage degradation,validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice.We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway.The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A,and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints.Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage,and could be potentially used for OA treatment.
基金supported by the National Natural Science Foundation of China (No. 30872716)the Natural Science Foundation of Hubei Province,China (No. 2015CFB288)Open Foundation of Hubei Province Key Laboratory of Tumor Microenvironment and immunotherapy (No. 2023KZL06)。
文摘Mitochondria play an important role in pressure overload-induced cardiac hypertrophy.The present study aimed to investigate the role of mitochondrial transient receptor potential vanilloid 3(TRPV3)in myocardial hypertrophy.A 0.7 mm diameter U-shaped silver clip was used to clamp the abdominal aorta of Sprague Dawley(SD)rats and establish an animal model of abdominal aortic constriction(AAC).Rat H9C2 myocardial cells were treated with angiotensin II(Ang II)to establish a hypertrophic myocardial cell model,and TRPV3 expression was knocked down using TRPV3 small interfering RNA(siRNA).JC-1 probe was used to detect mitochondrial membrane potential(MMP).DHE probe was used to detect ROS generation.Enzyme activities of mitochondrial respiratory chain complex I and III and ATP production were detected by assay kits.Immunofluorescence staining was used to detect TRPV3 expression in H9C2 cells.Western blot was used to detect the protein expression levels ofβ-myosin heavy chain(β-MHC),mitochondrial TRPV3 and mitochondrial NOX4.The results showed that,in the rat AAC model heart tissue and H9C2 cells treated with Ang II,the protein expression levels ofβ-MHC,mitochondrial TRPV3 and mitochondrial NOX4 were up-regulated,MMP was decreased,ROS generation was increased,mitochondrial respiratory chain complex I and III enzyme activities were decreased,and ATP production was reduced.After knocking down mitochondrial TRPV3 in H9C2 cells,the protein expression levels ofβ-MHC and mitochondrial NOX4 were down-regulated,MMP was increased,ROS generation was decreased,mitochondrial respiratory chain complex I and III enzyme activities were increased,and ATP production was increased.These results suggest that mitochondrial TRPV3 in cardiomyocytes exacerbates mitochondrial dysfunction by up-regulating NOX4,thereby participating in the process of pressure overload-induced myocardial hypertrophy.
基金supported by grants from the National Natural Science Foundation of China(Nos.81960732 and 82060733)the Natural Science Foundation of Jiangxi Province(No.20224BAB206111)+2 种基金the Science and Technology Plan of Jiangxi Provincial Health Commission(No.202311141)the Open Project of Jiangxi Provincial Key Laboratory of Drug Design and Evaluation(No.JKLDE-KF-2101)the Open Project of Key Laboratory of Modern Preparation of TCM,Ministry of Education,Jiangxi University of Chinese Medicine(No.TCM-201911).
文摘Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.
基金supported by grants from the National Natural Science Foundation of China(No.30872716)the Natural Science Foundation of Hubei Province(No.2015CFB288).
文摘Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction(AAC).Myocardial hypertrophy was evaluated by measuring the heart weight index(HW/BW),lung weight index(LW/BW),ratio of heart weight to tibia length(HW/TL),ratio of lung weight to tibia length(LW/TL),and cross-sectional area of myocardial cells.qRT-PCR was used to detect the mRNA expression of TRPV4.Western blotting was used to detect the protein expression of TRPV4,mast cell tryptase,myosin heavy chain beta(β-MHC),calcineurin A(CnA),and nuclear factor of activated T-cell c3(NFATc3).ELISA was used to measure the levels of brain natriuretic peptide(BNP)and histamine.Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.Results:Compared with those of the sham rats,the myocardial mast cells,tryptase,HW/BW,LW/BW,HW/TL,and LW/TL,the cross-sectional area of the myocardial cells,and the expression ofβ-MHC,TRPV4,CnA,and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly,whereas the MC stabilizer cromolyn sodium(CS)reversed these indicators.In H9c2 cardiomyocytes,treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4,β-MHC,BNP,CnA and NFATc3 and increased calcium ion influx,whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.Conclusion:Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine,and the Ca^(2+)/CnA/NFATc3 signaling pathway is involved in this process.
基金Supported by National Nature Science Foundation Project: 30973786supported by project of Education Department of Hubei Province: Q20101810
文摘Objective To study the neuroendocrine mechanisms of electroacupuncture （EA） at ＂Neiguan＂ （内关 PC 6） for preventing and treating myocardial hypertrophy. Methods Thirty 3-month-old Sprague-Dawley rats were randomly divided into a normal group, a model group and an EA group according to the random digit table, 10 in each group. Isoprenaline Hydrochloride （ISO） injection was subcutaneously injected to establish the model. EA at ＂Neiguan＂ （内关 PC 6） was applied for rats in the EA group, 20 min each time, once daily, for 14 successive days. No treatment was given to rats in the normal group and the observed. The plasma catecholamine neurotransmitters levels and c determined with high performance liquid chromatography model group. The electrocardiogram （ECG） was hanges of their metabolic products contents were （HLPC） method. Results Compared with the normal group, catecholamine neurotransmitters, such as epinephrin （E）, norepinephrine （NE）, and dopamine （DA） and metabolic products, such as 3-methoxy-4-hydroxyphenylglycol （MHPG）, homovanillic acid （HVA）, and 3,4-dihydroxy-phenyl acetic acid （DOPAC） were significantly increased in the model group （all P〈0.05）. These parameters decreased in the EA group when compared with the model group （all P〈0.05）. Conclusion EA at ＂Neiguan＂ （内关 PC 6） could improve the myocardial hypertrophy, which might be correlated with the neuroendocrine system.
基金Supported by Beijing Natural Science Foundation:Regulating effect of electroacupuncture on cardiac hypertrophy of spontaneously hypertensive rats based on PI3K/AKT signal transduction pathway(No.7162121)Young Teacher Program of Beijing University of Chinese Medicine:Mechanism of acupuncture on left ventricular remodeling in spontaneously hypertensive rats based on microRNA-195 targeting TGF/Smads signaling pathway(No.2017-JYB-JS-030)
文摘OBJECTIVE: To investigate the effects of electroacupuncture(EA) at Taichong(LR 3) and Baihui(DU 20)on myocardial hypertrophy in spontaneously hypertensive rats(SHRs).METHODS: Thirty-six SHRs were randomly assigned to model, EA, and Losartan groups, with twelve rats per group. Twelve Wistar Kyoto rats were selected as the normal control group. Systolic blood pressure(SBP) and cardiac function were measured in all rats.Expression levels of factors associated with the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR) pathway were evaluated by Western blotting and real-time PCR.Pathological changes of the heart tissue were observed by hematoxylin-eosin staining.RESULTS: After treatment, enhanced SBP was significantly decreased in the EA and Losartan groups compared with the model group(P < 0.01). Echocardiographic and morphological analyses revealed that enhanced end-diastolic interventricular septal thickness and left ventricular posterior wall thickness, as well as ratio of left ventricular weight to body weight were markedly diminished in the EA and Losartan groups(P < 0.01 or P < 0.05), while reduced left ventricular end-diastolic dimension and left ventricular ejection fraction were significantly ameliorated(P < 0.01). Real-time PCR and western blotting analyses showed that the expression levels of PI3K,Akt, and mT OR in SHRs were significantly up-regulated by EA and Losartan(P < 0.01), while the expression levels of PTEN and ANP were down-regulated(P < 0.01).CONCLUSION: EA at Taichong(LR 3) and Baihui(DU20) inhibited the development of cardiac hypertrophy and improved the cardiac function in SHRs, possibly through regulation of the PI3K/Akt/mTOR signalling pathway.
文摘Objective： To explore the effect and mechanism of matrine （Mt.） on myocardial interstitial fibrosis induced by pressure overload. Methods： Pressure overloaded myocardial hypertrophy was produced by banding of aorta abdominalis in 67 male Sprague-Dawley rats weighing （200±15） g. The rats were assigned into one of the following groups： sham-operation control, operation control, operation group treated with matrine （15 mg/（kg·d）） and treated with carvedilol （Car.） （3.6 mg/（kg·d）） group. The rats were given drugs one day after operation. Five weeks after treatment, the left ventricular weight （LVW） was measured and the volume of myocardial cells was detected with Hematoxylin-Eosin （H-E） stain and Masson stain was used to assess the level of fibrosis of the myocardial matrix. Myocardial metalloproteinase activity was quantified with zymography, and survival rate was calculated. Results： Survival rate significantly decreased （P〈0.05）, LVW/BW （body weight）, MMP-2 （matrix metalloproteinase-2） activity （P〈0.05）, size of cardiomyocytes and interstitial fibrosis obviously increased in the operation group compared with sham control group. Mr. and Car. treatment can significantly increase survival rate （P〈0.05）, decrease LVW/BW （P〈0.05） and MMP-2 activity （P〈0.05）, decrease size of cardiomyocytes and interstitial fibrosis compared with operation group. But there was difference compared with sham group. Conclusion： Matrine was shown to be able to prevent cardiac remodelling of bypertrophy cardium induced by pressure overload including myocardial hypertrophy and fibrosis which may be associated with the decrease in MMP-2 activity of heart.
基金supported by grants to A.M.(R01DK101730),V.D.(R01DK102815,R01DK114158),and M.W.(R01DK076116)from National Institute of Health
文摘During chronic kidney disease (CKD),alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality.The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization,but its effects in CKD are unknown.We tested the hypothesis that DMP1 supplementation in CKD would improve bone health,prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes.We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3^-/- mouse model of CKD.Col4a3^-/- mice demonstrated impaired kidney function,reduced bone DMP1 expression,reduced bone mass,altered osteocyte morphology and connectivity,increased osteocyte apoptosis,increased serum FGF23,hyperphosphatemia,left ventricular hypertrophy (LVH),and reduced survival.Genetic or pharmacological supplementation of DMP1 in Col4a3^-/- mice prevented osteocyte apoptosis,preserved osteocyte networks,corrected bone mass,partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription,and further increased serum phosphate.Despite impaired kidney function and worsened hyperphosphatemia,DMP1 prevented development of LVH and improved Col4a3^-/- survival.Our data suggest that CKD reduces DMP1 expression,whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.
文摘Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods： Forty male adult Sprague Dawley rats were divided into 5 groups One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1： sham group, rats （n=8） were gavaged with normal saline 2 ml/（kg·d） （ig）; Group 2： control group, rats （n=8） were treated with normal saline 2 ml/（kg·d） （ig）; Group 3： rats （n=8） were given perindopril 2 mg/（kg·d） （ig）; Group 4： rats （n=8） were treated with irbesartan 20 mg/（kg·d） （ig）; Group 5： rats （n=8） were given irbesartan 20 mg/（kg·d） plus perindopril 2 mg/（kg·d） （ig）. Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results： Left ventricular mass index （LVMI）, transverse diameter of myocardial cell （TDM）, calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca^2＋-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca^2＋-ATPase. Conclusion： These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca^2＋-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.
基金a grant from National Natural Sciences Foundation of China (No. 30500657)
文摘The changes of proto-oncogene c-fos and c-jun mRNA expression in angiotensin Ⅱ （AngⅡ）-induced hypertrophy and effects of sodium tanshinone ⅡA sulfonate （STS） in the primary culture of neonatal rat cardiomyocytes were investigated. Twelve neonatal clean grade Wistar rats were selected. The cardiomyocytes were isolated, cultured and divided according to different treatments in the medium. The cardiomyocyte size was determined by phase contrast microscope, and the rate of protein synthesis was measured by [3H]-Leucine incorporation. The c-fos and c-jun mRNA expression in cardiomyocytes was detected by reverse transcription polymerase chain reaction （RT-PCR）. It was found after cardiomyocytes were treated with AngⅡ for 30 min, the c-fos and c-jun mRNA expression in cardiomyocytes was increased significantly （P〈0.01）. After treatment with AngⅡ for 24 h, the rate of protein synthesis in AngⅡ group was significantly increased as compared with control group （P〈0.01）. After treatment with AngⅡ for 7 days, the size of cardiomyocytes in AngⅡ group was increased obviously as compared with control group （P〈0.05）. After pretreatment with STS or Valsartan before AngⅡ treatment, both of them could inhibit the above effects of AngⅡ （P〈0.05 or P〈0.01）. It was suggested that STS could ameliorate AngⅡ-induced cardiomyocyte hy- pertrophy by inhibiting c-fos and c-jun mRNA expression and reducing protein synthesis rate of cardiomyocytes.
基金supported in part by the following United States National Institute of Health grants: R01 grants (AR057022 and AR063071), R21 grant (AR059733 to MJH), a P30 Core Center grant (AR061307), and a T32 training grant that supported both AK and TPR (AR053459 to Regis J.O’Keefe and Michael J.Zuscik)
文摘RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.
