Pub Date : 2025-02-01DOI: 10.1016/j.yjmcc.2024.11.003
Jing Fu , Li Li , Long Chen , Congping Su , Xiuling Feng , Kai Huang , Laxi Zhang , Xiaoyan Yang , Qin Fu
{"title":"Corrigendum to “PGE2 protects against heart failure through inhibiting TGF-β1 synthesis in cardiomyocytes and crosstalk between TGF-β1 and GRK2” [Journal of Molecular and Cellular Cardiology. 172(2022) 63–77]","authors":"Jing Fu , Li Li , Long Chen , Congping Su , Xiuling Feng , Kai Huang , Laxi Zhang , Xiaoyan Yang , Qin Fu","doi":"10.1016/j.yjmcc.2024.11.003","DOIUrl":"10.1016/j.yjmcc.2024.11.003","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"199 ","pages":"Page 80"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.yjmcc.2024.11.012
Gregory Farber , Paige Takasugi , Shea Ricketts , Haofei Wang , Yifang Xie , Esther Farber , Jiandong Liu , Li Qian
Sox17-Erg direct reprogramming is a potent tool for the in vitro and in vivo generation of arterial-like induced-endothelial cells from fibroblasts. In this study, we illustrate the pioneering roles of both Sox17 and Erg in the endothelial cell reprogramming process and demonstrate that emergent gene expression only occurs when both factors are co-expressed. Bioinformatic analyses and molecular validation reveal both Bach2 and Etv4 as integral mediators of Sox17-Erg reprogramming with different roles in lung and heart fibroblast reprogramming. The generated organ-specific induced endothelial cells express molecular signatures similar to vasculature found in the starting cell's organ of origin and the starting chromatin architecture plays a role in the acquisition of this organ-specific identity. Overall, the Sox17-Erg reprogramming mechanism provides foundational knowledge for the future recapitulation of vascular heterogeneity through direct reprogramming.
{"title":"Sox17 and Erg synergistically activate endothelial cell fate in reprogramming fibroblasts","authors":"Gregory Farber , Paige Takasugi , Shea Ricketts , Haofei Wang , Yifang Xie , Esther Farber , Jiandong Liu , Li Qian","doi":"10.1016/j.yjmcc.2024.11.012","DOIUrl":"10.1016/j.yjmcc.2024.11.012","url":null,"abstract":"<div><div><em>Sox17-Erg</em> direct reprogramming is a potent tool for the in vitro and in vivo generation of arterial-like induced-endothelial cells from fibroblasts. In this study, we illustrate the pioneering roles of both <em>Sox17</em> and <em>Erg</em> in the endothelial cell reprogramming process and demonstrate that emergent gene expression only occurs when both factors are co-expressed. Bioinformatic analyses and molecular validation reveal both <em>Bach2</em> and <em>Etv4</em> as integral mediators of <em>Sox17-Erg</em> reprogramming with different roles in lung and heart fibroblast reprogramming. The generated organ-specific induced endothelial cells express molecular signatures similar to vasculature found in the starting cell's organ of origin and the starting chromatin architecture plays a role in the acquisition of this organ-specific identity. Overall, the <em>Sox17-Erg</em> reprogramming mechanism provides foundational knowledge for the future recapitulation of vascular heterogeneity through direct reprogramming.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"199 ","pages":"Pages 33-45"},"PeriodicalIF":4.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.yjmcc.2025.01.007
Parisa Shabani, Feng Dong, June Yun, Song Yi Shin, Amber Dinchman, Dipan Kundu, Adam Goodwill, James Gadd, Thomas Pucci, Christopher Kolz, Lindsay Shockling, Liya Yin, William Chilian, Vahagn Ohanyan
Heart failure (HF) is a conundrum in that, current therapies only slow the progression of the disease. We posit, if the causal mechanism were targeted, progression of the disease could be stopped and potentially reversed. We hypothesize that insufficient myocardial blood flow (MBF) produces minute areas of ischemia, that lead to an accumulating injury culminating in HF. Accordingly, we determined the relationship between MBF and cardiac work (wall stress-rate product [WSRP]) in control C57Bl6/J mice (Control), mice with transaortic constriction to produce HF (TAC-HF) and HF mice treated with the coronary vasodilator, chromonar (4 weeks of treatment, TAC-Chromonar). MBF and WSRP were measured during norepinephrine infusion in anesthetized mice. In Controls, MBF increased when work/WSRP was increased with norepinephrine, however, when cardiac work was increased in TAC-HF, MBF did not increase. After chromonar treatment, when work increased, MBF increased. Changes in cardiac function paralleled MBF, i.e., decrement in cardiac function occurred in TAC-HF (ejection fraction), but 4 weeks of chromonar treatment reversed this functional decline. We also found in a model of cardiac hypoxia fate-mapping, a 5-fold increase in the number of hypoxic cardiac myocytes (TAC-HF vs Control), which was reversed by chromonar. Capillary densities also followed this trend with a decrease from Control in TAC-HF, which was restored by Chromonar. We propose that a cause of HF is inadequate MBF to meet the metabolic demands of the working heart. Pharmacological coronary vasodilation with chromonar to increase MBF in HF can reverse the functional decline and improve cardiac function.
{"title":"Does coronary microvascular dysfunction play a role in heart failure with reduced ejection fraction?","authors":"Parisa Shabani, Feng Dong, June Yun, Song Yi Shin, Amber Dinchman, Dipan Kundu, Adam Goodwill, James Gadd, Thomas Pucci, Christopher Kolz, Lindsay Shockling, Liya Yin, William Chilian, Vahagn Ohanyan","doi":"10.1016/j.yjmcc.2025.01.007","DOIUrl":"10.1016/j.yjmcc.2025.01.007","url":null,"abstract":"<div><div>Heart failure (HF) is a conundrum in that, current therapies only slow the progression of the disease. We posit, if the causal mechanism were targeted, progression of the disease could be stopped and potentially reversed. We hypothesize that insufficient myocardial blood flow (MBF) produces minute areas of ischemia, that lead to an accumulating injury culminating in HF. Accordingly, we determined the relationship between MBF and cardiac work (wall stress-rate product [WSRP]) in control C57Bl6/J mice (Control), mice with transaortic constriction to produce HF (TAC-HF) and HF mice treated with the coronary vasodilator, chromonar (4 weeks of treatment, TAC-Chromonar). MBF and WSRP were measured during norepinephrine infusion in anesthetized mice. In Controls, MBF increased when work/WSRP was increased with norepinephrine, however, when cardiac work was increased in TAC-HF, MBF did not increase. After chromonar treatment, when work increased, MBF increased. Changes in cardiac function paralleled MBF, i.e., decrement in cardiac function occurred in TAC-HF (ejection fraction), but 4 weeks of chromonar treatment reversed this functional decline. We also found in a model of cardiac hypoxia fate-mapping, a 5-fold increase in the number of hypoxic cardiac myocytes (TAC-HF vs Control), which was reversed by chromonar. Capillary densities also followed this trend with a decrease from Control in TAC-HF, which was restored by Chromonar. We propose that a cause of HF is inadequate MBF to meet the metabolic demands of the working heart. Pharmacological coronary vasodilation with chromonar to increase MBF in HF can reverse the functional decline and improve cardiac function.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 61-67"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.yjmcc.2025.01.009
Langtao Wang , Jiarou Song , Zhen Yang , Hailong Zhang , Yaping Wang , Jin Liu , Sai Wang , Jian Shi , Xiaoyong Tong
Background and aim
Our previous research indicates that sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) dysfunction facilitates the phenotypic transformation of aortic smooth muscle cells (ASMCs) and intensifies aortic aneurysm through the regulation of calcium-dependent pathways and endoplasmic reticulum stress. Our hypothesis is that additional mechanisms are involved in aortic aneurysm and atherosclerosis induced by SERCA2 dysfunction from the perspective of ASMC phenotypic transformation.
Methods & results
In SERCA2 dysfunctional mice and their control littermates, ASMCs were isolated to analyze protein expression and cell functions, and angiotensin II was infused into these mice that were backcrossed into LDL receptor deficient background to induce aortic aneurysm and atherosclerosis. In ASMCs from SERCA2 dysfunctional mice, the cell cycle was accelerated, and proliferation and migration were enhanced, which could be reversed by SERCA agonist CDN1163 or calcium chelator BAPTA-AM. In ASMCs, SERCA2 dysfunction increased reactive oxygen species (ROS) production, activating extracellular signal-regulated kinases 1 and 2 (ERK1/2) and angiotensin II/angiotensin II type 1 receptor (AT1R) pathways. Both ERK1/2 and angiotensin II/AT1R activations are implicated in SERCA2 dysfunction-induced ASMC phenotypic transformation and ROS production. The redox modulator Tempol suppressed ERK1/2 and angiotensin II/AT1R pathways, inhibiting ASMC phenotypic transformation and alleviating angiotensin II-induced aortic aneurysm and atherosclerosis.
Conclusion
SERCA2 dysfunction accelerates aortic aneurysm and atherosclerosis by inducing oxidative stress in ASMCs, with activations of ERK1/2 and angiotensin II/AT1R involved in ASMC phenotypic transformation. Inhibition of oxidative stress in ASMCs is beneficial in alleviating angiotensin II-induced aortic aneurysm and atherosclerosis caused by SERCA2 dysfunction.
{"title":"SERCA2 dysfunction accelerates angiotensin II-induced aortic aneurysm and atherosclerosis by induction of oxidative stress in aortic smooth muscle cells","authors":"Langtao Wang , Jiarou Song , Zhen Yang , Hailong Zhang , Yaping Wang , Jin Liu , Sai Wang , Jian Shi , Xiaoyong Tong","doi":"10.1016/j.yjmcc.2025.01.009","DOIUrl":"10.1016/j.yjmcc.2025.01.009","url":null,"abstract":"<div><h3>Background and aim</h3><div>Our previous research indicates that sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) dysfunction facilitates the phenotypic transformation of aortic smooth muscle cells (ASMCs) and intensifies aortic aneurysm through the regulation of calcium-dependent pathways and endoplasmic reticulum stress. Our hypothesis is that additional mechanisms are involved in aortic aneurysm and atherosclerosis induced by SERCA2 dysfunction from the perspective of ASMC phenotypic transformation.</div></div><div><h3>Methods & results</h3><div>In SERCA2 dysfunctional mice and their control littermates, ASMCs were isolated to analyze protein expression and cell functions, and angiotensin II was infused into these mice that were backcrossed into LDL receptor deficient background to induce aortic aneurysm and atherosclerosis. In ASMCs from SERCA2 dysfunctional mice, the cell cycle was accelerated, and proliferation and migration were enhanced, which could be reversed by SERCA agonist CDN1163 or calcium chelator BAPTA-AM. In ASMCs, SERCA2 dysfunction increased reactive oxygen species (ROS) production, activating extracellular signal-regulated kinases 1 and 2 (ERK1/2) and angiotensin II/angiotensin II type 1 receptor (AT1R) pathways. Both ERK1/2 and angiotensin II/AT1R activations are implicated in SERCA2 dysfunction-induced ASMC phenotypic transformation and ROS production. The redox modulator Tempol suppressed ERK1/2 and angiotensin II/AT1R pathways, inhibiting ASMC phenotypic transformation and alleviating angiotensin II-induced aortic aneurysm and atherosclerosis.</div></div><div><h3>Conclusion</h3><div>SERCA2 dysfunction accelerates aortic aneurysm and atherosclerosis by inducing oxidative stress in ASMCs, with activations of ERK1/2 and angiotensin II/AT1R involved in ASMC phenotypic transformation. Inhibition of oxidative stress in ASMCs is beneficial in alleviating angiotensin II-induced aortic aneurysm and atherosclerosis caused by SERCA2 dysfunction.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 68-81"},"PeriodicalIF":4.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.yjmcc.2025.01.006
Brian P. Delisle , Abhilash Prabhat , Don E. Burgess , Isabel G. Stumpf , John J. McCarthy , Spencer B. Procopio , Xiping Zhang , Karyn A. Esser , Elizabeth A. Schroder
Cardiologists have analyzed daily patterns in the incidence of sudden cardiac death to identify environmental, behavioral, and physiological factors that trigger fatal arrhythmias. Recent studies have indicated an overall increase in sudden cardiac arrest during daytime hours when the frequency of arrhythmogenic triggers is highest. The risk of fatal arrhythmias arises from the interaction between these triggers such as elevated sympathetic signaling, catecholamine levels, heart rate, afterload, and platelet aggregation and the susceptibility of the heart (myocardial substrate) to them. A healthy myocardial substrate has structural and functional properties that protect against arrhythmias. However, individuals with cardiovascular disease often exhibit structural and electrophysiological alterations in the myocardial substrate that predispose them to sustained lethal arrhythmias. This review focuses on how day-night and circadian rhythms, both extrinsic and intrinsic, influence the protective properties of the myocardial substrate. Specifically, it explores recent advances in the temporal regulation of ion channel gene transcription, drawing on data from comprehensive bioinformatics resources (CircaDB, CircaAge, and CircaMET) and recent RNA sequencing studies. We also examine potential mechanisms underlying the temporal regulation of mRNA expression and the challenges in linking rhythmic mRNA expression to corresponding changes in protein levels. As chronobiological research in cardiology progresses, we anticipate the development of novel therapeutic strategies to enhance the protective properties of the myocardial substrate to reduce the risk of fatal arrhythmias and sudden cardiac arrest.
{"title":"Circadian influences on sudden cardiac death and cardiac electrophysiology","authors":"Brian P. Delisle , Abhilash Prabhat , Don E. Burgess , Isabel G. Stumpf , John J. McCarthy , Spencer B. Procopio , Xiping Zhang , Karyn A. Esser , Elizabeth A. Schroder","doi":"10.1016/j.yjmcc.2025.01.006","DOIUrl":"10.1016/j.yjmcc.2025.01.006","url":null,"abstract":"<div><div>Cardiologists have analyzed daily patterns in the incidence of sudden cardiac death to identify environmental, behavioral, and physiological factors that trigger fatal arrhythmias. Recent studies have indicated an overall increase in sudden cardiac arrest during daytime hours when the frequency of arrhythmogenic triggers is highest. The risk of fatal arrhythmias arises from the interaction between these triggers such as elevated sympathetic signaling, catecholamine levels, heart rate, afterload, and platelet aggregation and the susceptibility of the heart (myocardial substrate) to them. A healthy myocardial substrate has structural and functional properties that protect against arrhythmias. However, individuals with cardiovascular disease often exhibit structural and electrophysiological alterations in the myocardial substrate that predispose them to sustained lethal arrhythmias. This review focuses on how day-night and circadian rhythms, both extrinsic and intrinsic, influence the protective properties of the myocardial substrate. Specifically, it explores recent advances in the temporal regulation of ion channel gene transcription, drawing on data from comprehensive bioinformatics resources (CircaDB, CircaAge, and CircaMET) and recent RNA sequencing studies. We also examine potential mechanisms underlying the temporal regulation of mRNA expression and the challenges in linking rhythmic mRNA expression to corresponding changes in protein levels. As chronobiological research in cardiology progresses, we anticipate the development of novel therapeutic strategies to enhance the protective properties of the myocardial substrate to reduce the risk of fatal arrhythmias and sudden cardiac arrest.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 93-112"},"PeriodicalIF":4.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1016/j.yjmcc.2025.01.005
Yao Qu , Zhi-Xue Liu , Xiao-Xu Zheng , Sheng-Nan Wu , Jun-Qing An , Ming-Hui Zou , Zhi-Ren Zhang
Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.
Methods
Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition.
Results
Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca2+]M) levels, and impaired endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) signaling in HUVECs. In addition, sunitinib also decreased mitochondrial membrane potential, elongated mitochondria, and reduced MAMs. Remarkably, these effects were reversed by an adeno-virus linker (Ad-linker) that reinforces MAMs. Engineered augmentation of MAMs using AAV-FLT1-linker significantly mitigated sunitinib-induced hypertension, by restoring endothelium-dependent relaxation in mice, highlighting the crucial role of MAMs in this process. Further analyses revealed that sunitinib enhanced Akt-mediated expression of mitofusin 2 (MFN2), causing mitochondrial elongation, and induced dephosphorylation of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) at residues Y1737/Y1738, reducing [Ca2+]M. Our study suggests that increased MFN2 expression and IP3R1 dephosphorylation are critical in sunitinib-induced MAMs reduction and [Ca2+]M homeostasis.
Conclusion
Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IP3R1 dephosphorylation in endothelial cells, leading to endothelial dysfunction and hypertension. Our results provide the potential therapeutic targets for combating TKI-induced hypertension.
{"title":"MFN2-mediated decrease in mitochondria-associated endoplasmic reticulum membranes contributes to sunitinib-induced endothelial dysfunction and hypertension","authors":"Yao Qu , Zhi-Xue Liu , Xiao-Xu Zheng , Sheng-Nan Wu , Jun-Qing An , Ming-Hui Zou , Zhi-Ren Zhang","doi":"10.1016/j.yjmcc.2025.01.005","DOIUrl":"10.1016/j.yjmcc.2025.01.005","url":null,"abstract":"<div><div>Treatment of cancer patients with tyrosine kinase inhibitors (TKIs) often results in hypertension, but the underlying mechanism remains unclear. This study aimed to examine the role of mitochondrial morphology and function, particularly mitochondria-associated endoplasmic reticulum membranes (MAMs), in sunitinib-induced hypertension.</div></div><div><h3>Methods</h3><div>Both in vitro and in vivo experiments performed to assesse reactive oxygen species (ROS), nitric oxide (NO), endothelium-dependent vasorelaxation, systemic blood pressure, and mitochondrial function in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mouse aortic endothelial cells, under vehicle or sunitinib treatment condition<em>.</em></div></div><div><h3>Results</h3><div>Sunitinib increased mitochondrial ROS accumulation, decreased oxygen consumption rate, ATP production, and mitochondrial calcium ([Ca<sup>2+</sup>]<sub>M</sub>) levels, and impaired endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) signaling in HUVECs. In addition, sunitinib also decreased mitochondrial membrane potential, elongated mitochondria, and reduced MAMs. Remarkably, these effects were reversed by an adeno-virus linker (Ad-linker) that reinforces MAMs. Engineered augmentation of MAMs using AAV-FLT1-linker significantly mitigated sunitinib-induced hypertension, by restoring endothelium-dependent relaxation in mice, highlighting the crucial role of MAMs in this process. Further analyses revealed that sunitinib enhanced Akt-mediated expression of mitofusin 2 (MFN2), causing mitochondrial elongation, and induced dephosphorylation of inositol 1,4,5-trisphosphate receptor type 1 (IP<sub>3</sub>R1) at residues Y1737/Y1738, reducing [Ca<sup>2+</sup>]<sub>M</sub>. Our study suggests that increased MFN2 expression and IP<sub>3</sub>R1 dephosphorylation are critical in sunitinib-induced MAMs reduction and [Ca<sup>2+</sup>]<sub>M</sub> homeostasis.</div></div><div><h3>Conclusion</h3><div>Sunitinib induces mitochondrial dysfunction, Akt/MFN2-mediated decrease in MAMs and mitochondrial elongation, and IP<sub>3</sub>R1 dephosphorylation in endothelial cells, leading to endothelial dysfunction and hypertension. Our results provide the potential therapeutic targets for combating TKI-induced hypertension.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 45-60"},"PeriodicalIF":4.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1016/j.yjmcc.2025.01.003
Jiangying Kuang , Zhiyi Jia , Tou Kun Chong , Jian Chen , Kan Liu , Xin Wang , Zhaohua Li , Jing Zhang , Yanru Kong , Lin Deng , Martin Cadieras , Yuanyuan Sun , Rong Sun , Qinghua Lu , Yusheng Liu
Background
Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models.
Aim
This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro.
Methods
Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used isoprenaline (ISO)-induced TTS-like animal models, pre-treated with sac/val, to evaluate cardiac function and inflammatory response. Additionally, the effects of isoprenaline on cardiomyocytes and myocardial fibroblasts, as well as protection from rhBNP, were thoroughly studied.
Results
In TTS patients with a left ventricular ejection fraction (LVEF) ≤ 0.45, hyperglycemia, emotional stress, and inflammation were identified as independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. In TTS patients, sac/val reduced inflammation, evidenced by lower levels of white blood cells and interleukin 6, compared to patients who did not receive sac/val by day 30. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ1/Smad pathway.
Conclusions
This study revealed that sac/val decreased inflammatory responses, myocardial edema, and fibrosis, resulting in an increased percentage of survivors in the TTS group. Similar to findings from in vivo and in vitro experiments, sac/val exerted cardioprotective effects by reducing the inflammatory response and reversing myocardial remodeling mediated by the TLR4/NF-κB and TGFβ1/Smad pathways. In conclusion, these findings highlight the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.
{"title":"Sacubitril/valsartan attenuates inflammation and myocardial fibrosis in Takotsubo-like cardiomyopathy","authors":"Jiangying Kuang , Zhiyi Jia , Tou Kun Chong , Jian Chen , Kan Liu , Xin Wang , Zhaohua Li , Jing Zhang , Yanru Kong , Lin Deng , Martin Cadieras , Yuanyuan Sun , Rong Sun , Qinghua Lu , Yusheng Liu","doi":"10.1016/j.yjmcc.2025.01.003","DOIUrl":"10.1016/j.yjmcc.2025.01.003","url":null,"abstract":"<div><h3>Background</h3><div>Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models.</div></div><div><h3>Aim</h3><div>This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro.</div></div><div><h3>Methods</h3><div>Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used isoprenaline (ISO)-induced TTS-like animal models, pre-treated with sac/val, to evaluate cardiac function and inflammatory response. Additionally, the effects of isoprenaline on cardiomyocytes and myocardial fibroblasts, as well as protection from rhBNP, were thoroughly studied.</div></div><div><h3>Results</h3><div>In TTS patients with a left ventricular ejection fraction (LVEF) ≤ 0.45, hyperglycemia, emotional stress, and inflammation were identified as independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. In TTS patients, sac/val reduced inflammation, evidenced by lower levels of white blood cells and interleukin 6, compared to patients who did not receive sac/val by day 30. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ<sub>1</sub>/Smad pathway.</div></div><div><h3>Conclusions</h3><div>This study revealed that sac/val decreased inflammatory responses, myocardial edema, and fibrosis, resulting in an increased percentage of survivors in the TTS group. Similar to findings from in vivo and in vitro experiments, sac/val exerted cardioprotective effects by reducing the inflammatory response and reversing myocardial remodeling mediated by the TLR4/NF-κB and TGF<em>β</em><sub>1</sub>/Smad pathways. In conclusion, these findings highlight the anti-inflammatory and antifibrotic effects of sac/val in individuals with TTS.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 24-39"},"PeriodicalIF":4.9,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-08DOI: 10.1016/j.yjmcc.2025.01.001
Aileena C. Nelson , Thomas G. Molley , Gisselle Gonzalez , Natalie J. Kirkland , Alyssa R. Holman , Evan M. Masutani , Neil C. Chi , Adam J. Engler
Vinculin (VCL) is a key adapter protein located in force-bearing costamere complexes, which mechanically couples the sarcomere to the ECM. Heterozygous vinculin frameshift genetic variants can contribute to cardiomyopathy when external stress is applied, but the mechanosensitive pathways underpinning VCL haploinsufficiency remain elusive. Here, we show that in response to extracellular matrix stiffening, heterozygous loss of VCL disrupts force-mediated costamere protein recruitment, thereby impairing cardiomyocyte contractility and sarcomere organization. Analyses of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) harboring either VCL c.659dupA or VCL c.74del7 heterozygous VCL frameshift variants revealed that these VCL mutant hPSC-CMs exhibited heightened contractile strain energy, morphological maladaptation, and sarcomere disarray on stiffened matrix. Mechanosensitive recruitment of costameric talin 2, paxillin, focal adhesion kinase, and α-actinin was significantly reduced in vinculin variant cardiomyocytes. Despite poorly formed costamere complexes and sarcomeres, elevated expression of integrin β1 and cortical actin on stiff substrates may rescue force transmission on stiff substrates, an effect that is recapitulated in WT CMs by ligating integrin receptors and blocking mechanosensation. Together, these data support that heterozygous loss of VCL contributes to adverse cardiomyocyte remodeling by impairing adhesion-mediated force transmission from the costamere to the cytoskeleton. (191 words).
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Pub Date : 2025-01-04DOI: 10.1016/j.yjmcc.2024.12.011
Sahib S. Sarbjit-Singh , Samir W. Hamaia , Christopher A. Beaudoin , Christopher L.-H. Huang , Greg J. Mellor , Antony P. Jackson , Samantha C. Salvage
Introduction
Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterised by ST-segment elevation in the right precordial ECG leads and is associated with an increased risk of sudden cardiac death. We identify and characterise a novel SCN3B variant encoding the regulatory β3-subunit of the cardiac voltage-gated sodium channel, NaV1.5.
Methods and results
A 54-year-old Caucasian male presented with palpitations and dizziness. An ECG identified a spontaneous type 1 BrS pattern and review of his medical records revealed a prior type 1 BrS ECG. Next generation sequencing of a BrS risk panel of genes identified a novel SCN3B deletion (c. c412–414, p.T138Del) yielding a single amino acid deletion. No other pathogenic variants were identified. Using site-directed mutagenesis we made the β3-ΔT138 variant and examined structural and functional effects in a heterologous system. Computational predictions together with circular dichroism spectroscopy showed highly localised structural perturbations with minimal effect on the gross protein architecture. Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with NaV1.5. Electrophysiological analysis identified reduced peak current and channel availability. Additionally, an accelerated fast inactivation was observed only in the presence of both wild-type and ΔT138 β3-subunits, reflecting the heterozygous individual. These effects are consistent with a loss-of-function phenotype.
Conclusion
A novel BrS associated SCN3B deletion introduced minimally disruptive structural perturbations to the regulatory β3-subunit of NaV1.5, yet exerted significant electrophysiological effects. This variant highlights nuances of the NaV1.5-β3 interaction and its role in maintaining normal cardiac excitability.
{"title":"A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted NaV1.5 function","authors":"Sahib S. Sarbjit-Singh , Samir W. Hamaia , Christopher A. Beaudoin , Christopher L.-H. Huang , Greg J. Mellor , Antony P. Jackson , Samantha C. Salvage","doi":"10.1016/j.yjmcc.2024.12.011","DOIUrl":"10.1016/j.yjmcc.2024.12.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterised by ST-segment elevation in the right precordial ECG leads and is associated with an increased risk of sudden cardiac death. We identify and characterise a novel SCN3B variant encoding the regulatory β3-subunit of the cardiac voltage-gated sodium channel, Na<sub>V</sub>1.5.</div></div><div><h3>Methods and results</h3><div>A 54-year-old Caucasian male presented with palpitations and dizziness. An ECG identified a spontaneous type 1 BrS pattern and review of his medical records revealed a prior type 1 BrS ECG. Next generation sequencing of a BrS risk panel of genes identified a novel SCN3B deletion (c. c412–414, p.T138Del) yielding a single amino acid deletion. No other pathogenic variants were identified. Using site-directed mutagenesis we made the β3-ΔT138 variant and examined structural and functional effects in a heterologous system. Computational predictions together with circular dichroism spectroscopy showed highly localised structural perturbations with minimal effect on the gross protein architecture. Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with Na<sub>V</sub>1.5. Electrophysiological analysis identified reduced peak current and channel availability. Additionally, an accelerated fast inactivation was observed only in the presence of both wild-type and ΔT138 β3-subunits, reflecting the heterozygous individual. These effects are consistent with a loss-of-function phenotype.</div></div><div><h3>Conclusion</h3><div>A novel BrS associated SCN3B deletion introduced minimally disruptive structural perturbations to the regulatory β3-subunit of Na<sub>V</sub>1.5, yet exerted significant electrophysiological effects. This variant highlights nuances of the Na<sub>V</sub>1.5-β3 interaction and its role in maintaining normal cardiac excitability.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 11-23"},"PeriodicalIF":4.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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