Cardiac valve calcification is a common disease,especially among the elderly.Calcification can affect valve function and cause heart failure and sudden death(Adler et al.,2002).Aortic valve calcification is alsorelate...Cardiac valve calcification is a common disease,especially among the elderly.Calcification can affect valve function and cause heart failure and sudden death(Adler et al.,2002).Aortic valve calcification is alsorelated to arteriosclerosis and coronary heart disease(Rashedi et al.,2015).However,the origin of valve calcification is still unclear.This study characterized the展开更多
Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benef...Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benefit of antihypertensive drugs for CAVS.Methods Using genome-wide association studies(GWAS)summary statistics,we performed bidirectional two-sample univariable mendelian randomization(UVMR)to assess the causal associations of systolic blood pressure(SBP),diastolic blood pressure(DBP),and pulse pressure(PP)with CAVS.Multivariable mendelian randomization(MVMR)was conducted to evaluate the direct effect of hypertension on CAVS,adjusting for confounders.Drug target mendelian randomization(MR)and summary-level MR(SMR)were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk.Inverse variance weighting was the primary MR method,with sensitivity analyses to validate results.Results UVMR showed SBP,DBP,and PP have causal effects on CAVS,with no significant reverse causality.MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders.Drug-target MR analyses indicated that calcium channel blockers(CCBs),loop diuretics,and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk.SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk,while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk.Conclusions Hypertension has a causal relationship with CAVS.Managing SBP in hypertensive patients with CCBs may prevent CAVS.ARBs might exert protective effects on CAVS independent of blood pressure reduction.The relationship between diuretics and CAVS is complex,with opposite effects through different mechanisms.展开更多
Aortic valve calcification is a common disease in the elderly, but its cellular and molecular mechanisms are not clear. In order to verify the hypothesis that Wnt/β-catenin signaling pathway is involved in the proces...Aortic valve calcification is a common disease in the elderly, but its cellular and molecular mechanisms are not clear. In order to verify the hypothesis that Wnt/β-catenin signaling pathway is involved in the process of calcification of aortic valve, porcine aortic valve interstitial cells（VICs） were isolated, cultured and stimulated with oxidized low density lipoprotein（ox-LDL） for 48 h to induce the differentiation of VICs into osteoblast-like cells. The key proteins and genes of Wnt/β-catenin signaling pathway, such as glycogen synthase kinase 3β（GSK-3β） and β-catenin, were detected by using Western blotting and real-time polymerase chain reaction（PCR）. The results showed that the VICs managed to differentiate into osteoblast-like cells after the stimulation with ox-LDL and the levels of proteins and genes of GSK-3β and β-catenin were increased significantly in VICs after stimulation for 48 h（P0.05）. It is suggested that Wnt/β-catenin signaling pathway may play a key role in the differentiation of VICs into osteoblast-like cells and make great contribution to aortic valve calcification.展开更多
Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack...Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.展开更多
Objective To investigate the prevalence rate of heart valve calcification and its relativity with pathological changes and clinical pathogenic factors in elder patients at autopsy.Methods Pathology data at autopsy of ...Objective To investigate the prevalence rate of heart valve calcification and its relativity with pathological changes and clinical pathogenic factors in elder patients at autopsy.Methods Pathology data at autopsy of 1047patients with age from 60 to 106 years in Beijing Hospital from November 1954 to March 2016 were collected.Cases of heart valve calcification verified at autopsy展开更多
Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We ...Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We bypothesized that the Aβ40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell(VIC)phenotype,and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells(AVICs)by inhibiting the extracellular-regulated kinase1/2(ERK 1/2)/nuclear factor kappa-B(NF-kB)signaling pathway.To test this hypothesis,the activation of AB40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining.Cultured calcific VIC models were used in vitro.The VICs were stimulated using Aβ40,with or without RAGE small interfering ribonucleic acid(siRNA),and ERK1/2 and NF-κB inhibitors for analysis.Our data revealed that AB40 induced the ERK 1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.展开更多
Calcification of the aortic valve is a prevalent cardiovascular pathology in the aging population.Traditionally linked to inflammation,lipid accumulation,and risk conditions,this disease remains poorly understood,and ...Calcification of the aortic valve is a prevalent cardiovascular pathology in the aging population.Traditionally linked to inflammation,lipid accumulation,and risk conditions,this disease remains poorly understood,and effective treatments to halt its progression are not yet available.We hypothesized that calcification of the human valve interstitial cells(VICs)is associated with cellular senescence and alterations in the epigenetic setup,like in arteries.To verify this hypothesis,we examined the epigenetic marks(DNA methylation;Histones H3/H4 acetylation/methylation),the senescence and the calcification process in human VICs obtained from two distinct pathologic settings of the aortic valve(valve insufficiency and valve stenosis),and employed a mouse model of vascular/valve calcification,based on the administration of Vitamin D.Our findings revealed a link between the senescent phenotype of human VICs and calcification,characterized by increased DNA methylation and changes in histone epigenetic marks.To reverse the senescent/calcific VICs phenotype,we used Pentadecylidenemalonate-1b(SPV106),which activates KAT2B/pCAF histone acetyltransferase.In human VICs,SPV106 restored Histone acetylation marks,modified general chromatin accessibility and upregulated expression of Notch1,a potent inhibitor of valve calcification.The treatment also prevented the accumulation of calcific lesions in an ex vivo model of aortic valve calcification.In vivo treatment with SPV106 reduced calcification of the valve induced by administering Vitamin-D and positively preserved the valve motion compromised by calcification and the overall cardiac function.Based on these results,we propose the treatment with activators of histone acetylates as a viable option to prevent senescence/calcification of aortic VICs via restoration of correct chromatin acetylation,with concrete hopes to retard the progression of valve stenosis,a still largely unmet therapeutic need.展开更多
In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated wi...In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.展开更多
Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for is...Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.展开更多
Calcific Aortic Valve Disease(CAVD)is prevalent among the elderly as the most common valvular heart disease.Cur-rently,no pharmaceutical interventions can effectively reverse or prevent CAVD,making valve replacement t...Calcific Aortic Valve Disease(CAVD)is prevalent among the elderly as the most common valvular heart disease.Cur-rently,no pharmaceutical interventions can effectively reverse or prevent CAVD,making valve replacement the pri-mary therapeutic recourse.Extensive research spanning decades has contributed to the establishment of animal and in vitro cell models,which facilitates a deeper understanding of the pathophysiological progression and underly-ing mechanisms of CAVD.In this review,we provide a comprehensive summary and analysis of the strengths and limi-tations associated with commonly employed models for the study of valve calcification.We specifically emphasize the advancements in three-dimensional culture technologies,which replicate the structural complexity of the valve.Furthermore,we delve into prospective recommendations for advancing in vivo and in vitro model studies of CAVD.展开更多
Objective:Calcific aortic valve disease(CAVD)affects millions of elderly people,and there is currently no effective way to stop or slow down its progression.Therefore,exploring the pathogenesis of CAVD is very importa...Objective:Calcific aortic valve disease(CAVD)affects millions of elderly people,and there is currently no effective way to stop or slow down its progression.Therefore,exploring the pathogenesis of CAVD is very important for prevention and treatment.Cartilage oligomeric matrix protein(COMP)have important role in cell phenotype change.This study is aimed to confirm whether COMP participate in CAVD and try to find the possible mechanisms.Methods:Human aortic valve tissues from Nanjing First Hospital(CAVD group,n=20;control group,n=11)were harvested.The expression level of COMP was tested by western blot and immunohistochemistry.Dual immunofluorescence staining was used for locating COMP.Bone morphogenetic protein-2(BMP2)signalling were tested by western blot.The animal model was also used to detect COMP level by immunohistochemistry.Results:The results showed that the expression level of COMP was significantly increased in the calcific valve samples when compared with that of the control valve(P<0.05);COMP was expressed near the calcific nodules and co-localized with a-smooth muscle actin(a-SMA).The protein levels of BMP2 and p-Smads 1/5/9 were markedly more highly expressed in the CAVD group than the control group(P<0.05).Furthermore,immunofluorescence detection showed that COMP and BMP2 were co-located in calcific valves.Conclusions:The above results suggested that upregulation of COMP and BMP2 may be associated with aortic valve calcification and that COMP may become a potential therapeutic target in human CAVD.展开更多
基金supported by the National Natural Science Foundation of China(Grant NO.40972210,41272048)
文摘Cardiac valve calcification is a common disease,especially among the elderly.Calcification can affect valve function and cause heart failure and sudden death(Adler et al.,2002).Aortic valve calcification is alsorelated to arteriosclerosis and coronary heart disease(Rashedi et al.,2015).However,the origin of valve calcification is still unclear.This study characterized the
基金supported by the National Natural Science Foundation of China(82170375,U23A20395)1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(ZYGD23021,23HXF-H009)Sichuan Science and Technology Program 2023NSFSC1645。
文摘Background Hypertension is associated with an increased risk of calcific aortic valve stenosis(CAVS).However,the directionality of causation between blood pressure traits and aortic stenosis is unclear,as is the benefit of antihypertensive drugs for CAVS.Methods Using genome-wide association studies(GWAS)summary statistics,we performed bidirectional two-sample univariable mendelian randomization(UVMR)to assess the causal associations of systolic blood pressure(SBP),diastolic blood pressure(DBP),and pulse pressure(PP)with CAVS.Multivariable mendelian randomization(MVMR)was conducted to evaluate the direct effect of hypertension on CAVS,adjusting for confounders.Drug target mendelian randomization(MR)and summary-level MR(SMR)were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk.Inverse variance weighting was the primary MR method,with sensitivity analyses to validate results.Results UVMR showed SBP,DBP,and PP have causal effects on CAVS,with no significant reverse causality.MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders.Drug-target MR analyses indicated that calcium channel blockers(CCBs),loop diuretics,and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk.SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk,while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk.Conclusions Hypertension has a causal relationship with CAVS.Managing SBP in hypertensive patients with CCBs may prevent CAVS.ARBs might exert protective effects on CAVS independent of blood pressure reduction.The relationship between diuretics and CAVS is complex,with opposite effects through different mechanisms.
基金supported by the National Natural Science Foundation of China(No.81070190)
文摘Aortic valve calcification is a common disease in the elderly, but its cellular and molecular mechanisms are not clear. In order to verify the hypothesis that Wnt/β-catenin signaling pathway is involved in the process of calcification of aortic valve, porcine aortic valve interstitial cells（VICs） were isolated, cultured and stimulated with oxidized low density lipoprotein（ox-LDL） for 48 h to induce the differentiation of VICs into osteoblast-like cells. The key proteins and genes of Wnt/β-catenin signaling pathway, such as glycogen synthase kinase 3β（GSK-3β） and β-catenin, were detected by using Western blotting and real-time polymerase chain reaction（PCR）. The results showed that the VICs managed to differentiate into osteoblast-like cells after the stimulation with ox-LDL and the levels of proteins and genes of GSK-3β and β-catenin were increased significantly in VICs after stimulation for 48 h（P0.05）. It is suggested that Wnt/β-catenin signaling pathway may play a key role in the differentiation of VICs into osteoblast-like cells and make great contribution to aortic valve calcification.
基金National Natural Science Foundation of China,Grant/Award Number:81770252,82030014,82271606 and U22A20267Binjiang Institute of Zhejiang University,Grant/Award Number:ZY202205SMKY001Key Program of Major Science and Technology Projects in Zhejiang Province,Grant/Award Number:2021C03097 and 2022C03063。
文摘Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.
文摘Objective To investigate the prevalence rate of heart valve calcification and its relativity with pathological changes and clinical pathogenic factors in elder patients at autopsy.Methods Pathology data at autopsy of 1047patients with age from 60 to 106 years in Beijing Hospital from November 1954 to March 2016 were collected.Cases of heart valve calcification verified at autopsy
基金This study was supported by the National Natural Science Foundation of China(No.81800343).
文摘Amyloid beta(AB)peptide 40 enhances the activation of receptor for advanced glycation end products(RAGE)in immune-inflammatory diseases.RAGE exhibits several ffects in the setting of numerous cardiovascular events.We bypothesized that the Aβ40/RAGE pathway is involved in the osteoblastic differentiation of the valvular interstitial cell(VIC)phenotype,and RAGE knockout intervention could reduce the calcification of aortic valve interstitial cells(AVICs)by inhibiting the extracellular-regulated kinase1/2(ERK 1/2)/nuclear factor kappa-B(NF-kB)signaling pathway.To test this hypothesis,the activation of AB40/RAGE pathway in human calcific AVs was evaluated with immunohistochemical staining.Cultured calcific VIC models were used in vitro.The VICs were stimulated using Aβ40,with or without RAGE small interfering ribonucleic acid(siRNA),and ERK1/2 and NF-κB inhibitors for analysis.Our data revealed that AB40 induced the ERK 1/2/NF-κB signaling pathway and osteoblastic differentiation of AVICs via the RAGE pathway in vitro.
基金funded by Ricerca Corrente and Ricerca 5 per 1000 program grants(MP).
文摘Calcification of the aortic valve is a prevalent cardiovascular pathology in the aging population.Traditionally linked to inflammation,lipid accumulation,and risk conditions,this disease remains poorly understood,and effective treatments to halt its progression are not yet available.We hypothesized that calcification of the human valve interstitial cells(VICs)is associated with cellular senescence and alterations in the epigenetic setup,like in arteries.To verify this hypothesis,we examined the epigenetic marks(DNA methylation;Histones H3/H4 acetylation/methylation),the senescence and the calcification process in human VICs obtained from two distinct pathologic settings of the aortic valve(valve insufficiency and valve stenosis),and employed a mouse model of vascular/valve calcification,based on the administration of Vitamin D.Our findings revealed a link between the senescent phenotype of human VICs and calcification,characterized by increased DNA methylation and changes in histone epigenetic marks.To reverse the senescent/calcific VICs phenotype,we used Pentadecylidenemalonate-1b(SPV106),which activates KAT2B/pCAF histone acetyltransferase.In human VICs,SPV106 restored Histone acetylation marks,modified general chromatin accessibility and upregulated expression of Notch1,a potent inhibitor of valve calcification.The treatment also prevented the accumulation of calcific lesions in an ex vivo model of aortic valve calcification.In vivo treatment with SPV106 reduced calcification of the valve induced by administering Vitamin-D and positively preserved the valve motion compromised by calcification and the overall cardiac function.Based on these results,we propose the treatment with activators of histone acetylates as a viable option to prevent senescence/calcification of aortic VICs via restoration of correct chromatin acetylation,with concrete hopes to retard the progression of valve stenosis,a still largely unmet therapeutic need.
基金supported by grants from the National Nature Science Foundation of China(No.81070190)the Foundation of Natural Sciences of Hubei Province of China(No.2014CFB962)
文摘In order to investigate the roles of Wnt signal pathway in transformation of cardiac valvular myofibroblasts to the osteoblast-like phenotype, the primary cultured porcine aortic valve myofibroblasts were incubated with oxidized low density lipoprotein（ox-LDL, 50 mg/L）, and divided into four groups according to the ox-LDL treatment time： control group, ox-LDL 24-h group, ox-LDL 48-h group, and ox-LDL 72-h group. Wnt signal pathway blocker Dickkopf-1（DDK-1, 100 μg/L） was added in ox-LDL 72-h group. The expression of α-smooth muscle actin（α-SMA）, bone morphogenetic protein 2（BMP2）, alkaline phosphatase（ALP）, and osteogenic transcription factor Cbfa-1 was detected by Western blotting, and that of β-catenin, a key mediator of Wnt signal pathway by immunocytochemical staining method. The Wnt/β-catenin was observed and the transformation of myofibroblasts to the osteoblast-like phenotype was examined. The expression of α-SMA, BMP2, ALP and Cbfa-1 proteins in the control group was weaker than in the ox-LDL-treated groups. In ox-LDL-treated groups, the protein expression of α-SMA, BMP2, ALP, and Cbfa-1 was significantly increased in a time-dependent manner as compared with the control group, and there was significant difference among the three ox-LDL-treated groups（P〈0.05 for all）; β-catenin protein was also up-regulated in the ox-LDL-treated groups in a time-dependent manner as compared with the control group（P〈0.05）, and its transfer from cytoplasm to nucleus and accumulation in the nucleus were increased in the same fashion（P〈0.05）. After addition of DKK-1, the expression of α-SMA, bone-related proteins and β-catenin protein was significantly reduced as compared with ox-LDL 72-h group（P〈0.05）. The Wnt/ β-catenin signaling pathway may play an important role in transformation of valvular myofibroblasts to the osteoblast-like phenotype.
文摘Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.
基金National Key R&D Program of China to D.Z.(2021YFA1101902)National Natural Science Foundation of China to D.Z.(32171107)+2 种基金J.P.(82300301,U23A20399)Open Funding Project of the State Key Laboratory of Biocatalysis and Enzyme Engineering(SKLBEE2021009)the Fundamental Research Funds for the Central Universities(3332022022).
文摘Calcific Aortic Valve Disease(CAVD)is prevalent among the elderly as the most common valvular heart disease.Cur-rently,no pharmaceutical interventions can effectively reverse or prevent CAVD,making valve replacement the pri-mary therapeutic recourse.Extensive research spanning decades has contributed to the establishment of animal and in vitro cell models,which facilitates a deeper understanding of the pathophysiological progression and underly-ing mechanisms of CAVD.In this review,we provide a comprehensive summary and analysis of the strengths and limi-tations associated with commonly employed models for the study of valve calcification.We specifically emphasize the advancements in three-dimensional culture technologies,which replicate the structural complexity of the valve.Furthermore,we delve into prospective recommendations for advancing in vivo and in vitro model studies of CAVD.
基金the general program of Science and Technology Development Foundation of Nanjing Medical University(No.NMUB2018314)Jiangsu Provincial Key Medical Discipline(Laboratory)(ZDXKA2016021).
文摘Objective:Calcific aortic valve disease(CAVD)affects millions of elderly people,and there is currently no effective way to stop or slow down its progression.Therefore,exploring the pathogenesis of CAVD is very important for prevention and treatment.Cartilage oligomeric matrix protein(COMP)have important role in cell phenotype change.This study is aimed to confirm whether COMP participate in CAVD and try to find the possible mechanisms.Methods:Human aortic valve tissues from Nanjing First Hospital(CAVD group,n=20;control group,n=11)were harvested.The expression level of COMP was tested by western blot and immunohistochemistry.Dual immunofluorescence staining was used for locating COMP.Bone morphogenetic protein-2(BMP2)signalling were tested by western blot.The animal model was also used to detect COMP level by immunohistochemistry.Results:The results showed that the expression level of COMP was significantly increased in the calcific valve samples when compared with that of the control valve(P<0.05);COMP was expressed near the calcific nodules and co-localized with a-smooth muscle actin(a-SMA).The protein levels of BMP2 and p-Smads 1/5/9 were markedly more highly expressed in the CAVD group than the control group(P<0.05).Furthermore,immunofluorescence detection showed that COMP and BMP2 were co-located in calcific valves.Conclusions:The above results suggested that upregulation of COMP and BMP2 may be associated with aortic valve calcification and that COMP may become a potential therapeutic target in human CAVD.
