Aims Vascular smooth muscle cell (VSMC) apoptosis plays a key role in the development of thoracic aortic aneurysm and dissection (TAAD), a lethal cardiovascular disease with high mortality rates but limited pharmacological therapy. BMAL1 dysregulation is associated with apoptosis. However, it remains elusive whether BMAL1 dysregulation may aggravate VSMC apoptosis to participate in the development of TAAD. Methods and Results Transcriptomic analysis and molecular assays were performed to analyze BMAL1 level in the TAAD patients and 3-aminopropionitrile fumarate (BAPN)-induced TAAD mice. Global and VSMC-specific BMAL1 haploinsufficient mice were used to determine the role of BMAL1 in BAPN-induced TAAD murine model. Transcriptomics, spatial transcriptomics, histological, and in vitro experiments were performed to examine the underlying mechanisms. BMAL1 level was reduced in the thoracic aorta from TAAD patients and BAPN-challenged mice. Global and VSMC-specific BMAL1 haploinsufficiency significantly increased the risk of BAPN-induced TAAD in mice. BMAL1 dysregulation induced VSMC apoptosis during challenge-induced TAAD formation. Moreover, BMAL1 transcriptionally regulated REV-ERBα by binding to the E-box in its promoter region. Overexpression of REV-ERBα alleviated the detrimental effect of BMAL1 dysregulation on the formation of TAAD and VSMC apoptosis. Conversely, REV-ERBα dysregulation aggravated TAAD and VSMC apoptosis. Mechanistically, VSMC apoptosis inducer c-MYC was regulated by BMAL1/REV-ERBα axis and was proven as a direct target of REV-ERBα. Importantly, BMAL1 activator ISX-9 and REV-ERBα agonist SR9009 reduced the risk of BAPN-induced TAAD in both BMAL1 haploinsufficient and control mice, even when they were administered from 14 days after BAPN modeling. Conclusions BMAL1 insufficiency increases the risk of TAAD by inducing VSMC apoptosis via downregulation of REV-ERBα. BMAL1 and REV-ERBα may serve as pharmacological targets for TAAD prevention and therapy.
{"title":"BMAL1 insufficiency increases the risk of thoracic aortic aneurysm and dissection","authors":"Wenyu Song, Guangguo Fu, Qing Li, Chunxiu Huo, Liwan Xiao, Meiqi Liu, Xueting Zhang, Huanhuan Sun, Kangjie Shen, Lijie Shi, Lingyan Ni, Peiyi Zhou, Liqi Huang, Lieyang Qin, Hao Lai, Chunsheng Wang, Yun-Chi Tang, Jinmiao Chen, Hung-Chun Chang, Lai Wei","doi":"10.1093/cvr/cvaf259","DOIUrl":"https://doi.org/10.1093/cvr/cvaf259","url":null,"abstract":"Aims Vascular smooth muscle cell (VSMC) apoptosis plays a key role in the development of thoracic aortic aneurysm and dissection (TAAD), a lethal cardiovascular disease with high mortality rates but limited pharmacological therapy. BMAL1 dysregulation is associated with apoptosis. However, it remains elusive whether BMAL1 dysregulation may aggravate VSMC apoptosis to participate in the development of TAAD. Methods and Results Transcriptomic analysis and molecular assays were performed to analyze BMAL1 level in the TAAD patients and 3-aminopropionitrile fumarate (BAPN)-induced TAAD mice. Global and VSMC-specific BMAL1 haploinsufficient mice were used to determine the role of BMAL1 in BAPN-induced TAAD murine model. Transcriptomics, spatial transcriptomics, histological, and in vitro experiments were performed to examine the underlying mechanisms. BMAL1 level was reduced in the thoracic aorta from TAAD patients and BAPN-challenged mice. Global and VSMC-specific BMAL1 haploinsufficiency significantly increased the risk of BAPN-induced TAAD in mice. BMAL1 dysregulation induced VSMC apoptosis during challenge-induced TAAD formation. Moreover, BMAL1 transcriptionally regulated REV-ERBα by binding to the E-box in its promoter region. Overexpression of REV-ERBα alleviated the detrimental effect of BMAL1 dysregulation on the formation of TAAD and VSMC apoptosis. Conversely, REV-ERBα dysregulation aggravated TAAD and VSMC apoptosis. Mechanistically, VSMC apoptosis inducer c-MYC was regulated by BMAL1/REV-ERBα axis and was proven as a direct target of REV-ERBα. Importantly, BMAL1 activator ISX-9 and REV-ERBα agonist SR9009 reduced the risk of BAPN-induced TAAD in both BMAL1 haploinsufficient and control mice, even when they were administered from 14 days after BAPN modeling. Conclusions BMAL1 insufficiency increases the risk of TAAD by inducing VSMC apoptosis via downregulation of REV-ERBα. BMAL1 and REV-ERBα may serve as pharmacological targets for TAAD prevention and therapy.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"97 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Boyan Zhang, Natalia Loaiza, Antoine Rimbert, Federico Oldoni, Lisanne L Blauw, Patrick C N Rensen, Laurent O Martinez, Jerome Robert, Arnold von Eckardstein, Justina Clarinda Wolters, Nicolette Huijkman, Niels Kloosterhuis, Marieke Smit, Bart van de Sluis, Jan Albert Kuivenhoven, Umesh Tharehalli
Aims In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unraveled. Methods and Results Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with MEK1 inhibitor to block ERK. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to study HDL size and composition in human cohort studies. Studies in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (no changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell-surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. Conclusions This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational upregulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolemia will not only lower plasma levels of LDL cholesterol but also HDL cholesterol.
{"title":"Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational upregulation of SR-B1 protein levels","authors":"Boyan Zhang, Natalia Loaiza, Antoine Rimbert, Federico Oldoni, Lisanne L Blauw, Patrick C N Rensen, Laurent O Martinez, Jerome Robert, Arnold von Eckardstein, Justina Clarinda Wolters, Nicolette Huijkman, Niels Kloosterhuis, Marieke Smit, Bart van de Sluis, Jan Albert Kuivenhoven, Umesh Tharehalli","doi":"10.1093/cvr/cvaf254","DOIUrl":"https://doi.org/10.1093/cvr/cvaf254","url":null,"abstract":"Aims In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unraveled. Methods and Results Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with MEK1 inhibitor to block ERK. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to study HDL size and composition in human cohort studies. Studies in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (no changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell-surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. Conclusions This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational upregulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolemia will not only lower plasma levels of LDL cholesterol but also HDL cholesterol.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"19 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Remembering Dr. Gary D. Lopaschuk, PhD (1956-2025).","authors":"Jason R B Dyck","doi":"10.1093/cvr/cvaf260","DOIUrl":"https://doi.org/10.1093/cvr/cvaf260","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"111 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nucleoporin 35: a novel nuclear pore complex protein involved in pathological cardiac remodeling.","authors":"Marie Louise Ndzie Noah,Jun Yoshioka","doi":"10.1093/cvr/cvaf191","DOIUrl":"https://doi.org/10.1093/cvr/cvaf191","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"75 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariel Cano-Jorge, Sofia Gómez, Jaap den Toonder, Ye Wang, Robert Passier
The use of human pluripotent stem cells in cardiac tissue engineering has led to significant advances in the development of in vitro models of the human heart. However, full maturation of human pluripotent stem cell derived cardiomyocytes has not been achieved. Current maturation strategies aim to replicate the native cardiac environment by incorporating the passive and active mechanical cues of the heart. Cardiac preload and afterload are key active mechanical loads that directly influence cardiomyocyte maturation and overall cardiac function. In this review, we explore the role of mechanical stimuli in cardiac development and cardiomyocyte maturation, with a focus on how preload and afterload dynamics can be replicated in vitro using platforms such as engineered heart tissues, stretchable membranes, bioactuators, engineered cardiac chambers, and microtissues. Additionally, we highlight the role of stimulation parameters used in dynamic preload modelling and how the incorporation of these active mechanical loads is applied in disease modelling.
{"title":"In vitro approaches to mimic cardiac mechanical load dynamics for enhancing maturation and disease modelling","authors":"Mariel Cano-Jorge, Sofia Gómez, Jaap den Toonder, Ye Wang, Robert Passier","doi":"10.1093/cvr/cvaf247","DOIUrl":"https://doi.org/10.1093/cvr/cvaf247","url":null,"abstract":"The use of human pluripotent stem cells in cardiac tissue engineering has led to significant advances in the development of in vitro models of the human heart. However, full maturation of human pluripotent stem cell derived cardiomyocytes has not been achieved. Current maturation strategies aim to replicate the native cardiac environment by incorporating the passive and active mechanical cues of the heart. Cardiac preload and afterload are key active mechanical loads that directly influence cardiomyocyte maturation and overall cardiac function. In this review, we explore the role of mechanical stimuli in cardiac development and cardiomyocyte maturation, with a focus on how preload and afterload dynamics can be replicated in vitro using platforms such as engineered heart tissues, stretchable membranes, bioactuators, engineered cardiac chambers, and microtissues. Additionally, we highlight the role of stimulation parameters used in dynamic preload modelling and how the incorporation of these active mechanical loads is applied in disease modelling.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"182 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The paradox of MTHFD2 activity in cardiac inflammation.","authors":"M Paula Longhi,Federica M Marelli-Berg","doi":"10.1093/cvr/cvaf251","DOIUrl":"https://doi.org/10.1093/cvr/cvaf251","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"100 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AIMSCardiac aging is characterized by endothelial dysfunction and associated cardiovascular pathologies, often involving endothelial-to-mesenchymal transition (EndoMT) in cardiac endothelial cells. While the transcription factor Ets2, a member of the Ets family, is known to regulate endothelial cell survival and function, its role in EndoMT and cardiac aging remains poorly understood.METHODS AND RESULTSTo investigate this, we utilized single-nucleus RNA sequencing (snRNA-Seq) in Ets2-super-enhancer (Ets2-SE)-deficient mice to examine the regulation of Ets2 expression across various cardiac cell types. We assessed the relationship between Ets2 expression and heart aging, and evaluated the characteristics of cardiac aging in Ets2-SE-deficient mice. Furthermore, we generated endothelial cell-specific Ets2 knockout mice (ECKO) to investigate the role of Ets2 in EndoMT of cardiac endothelial cells both in vitro and in vivo.Our results establish a link between decreased Ets2 expression and the development of aging-associated cardiac pathological remodeling. Through data analyses, we identified a super-enhancer (Ets2-SE) that regulates Ets2 expression in the heart. Ets2-SE-deficient mice exhibited significantly lower Ets2 expression in cardiac tissues and displayed advanced aging phenotypes, including increased cardiac fibrosis and dysfunction, compared to wild-type controls. SnRNA-Seq analyses revealed a remarkable downregulation of Ets2 in endothelial cells, correlating with the activation of EndoMT. Furthermore, endothelial-specific deletion of Ets2 exacerbated aging and myocardial infarction-induced cardiac fibrosis and heart dysfunction. Mechanistic studies demonstrated that silencing ETS2 in human umbilical vein endothelial cells (HUVECs) promotes EndoMT by transcriptionally suppressing the endothelial marker gene TIE1. This transition is accompanied by endothelial cell senescence and the activation of the senescence-associated secretory phenotype (SASP), which contributes to myocardial fibrosis and cardiac aging, partially mediated by Serpine1. These findings identify Ets2 as a critical regulator of EndoMT in the context of cardiac aging.CONCLUSIONSOur findings reveal that the Ets2 super-enhancer regulates Ets2 expression in cardiac endothelial cells, modulating heart aging and EndoMT. Ets2's regulation of endothelial marker genes, especially TIE1, plays a pivotal role in mitigating EndoMT and preventing senescence in cardiac vascular endothelial cells, suggesting potential therapeutic targets for addressing cardiovascular aging.
{"title":"The Ets2 super-enhancer modulates endothelial-mesenchymal transition during cardiac aging.","authors":"Zhenglong Guo,Lan Li,Junwei Luo,Wei Xue,Shasha Bian,Yongchang Zhu,Dawei Huo,Wenke Yang,Jing Ma,Yibin Hao,Guanwei Fan,Bingtao Hao,Shixiu Liao","doi":"10.1093/cvr/cvaf242","DOIUrl":"https://doi.org/10.1093/cvr/cvaf242","url":null,"abstract":"AIMSCardiac aging is characterized by endothelial dysfunction and associated cardiovascular pathologies, often involving endothelial-to-mesenchymal transition (EndoMT) in cardiac endothelial cells. While the transcription factor Ets2, a member of the Ets family, is known to regulate endothelial cell survival and function, its role in EndoMT and cardiac aging remains poorly understood.METHODS AND RESULTSTo investigate this, we utilized single-nucleus RNA sequencing (snRNA-Seq) in Ets2-super-enhancer (Ets2-SE)-deficient mice to examine the regulation of Ets2 expression across various cardiac cell types. We assessed the relationship between Ets2 expression and heart aging, and evaluated the characteristics of cardiac aging in Ets2-SE-deficient mice. Furthermore, we generated endothelial cell-specific Ets2 knockout mice (ECKO) to investigate the role of Ets2 in EndoMT of cardiac endothelial cells both in vitro and in vivo.Our results establish a link between decreased Ets2 expression and the development of aging-associated cardiac pathological remodeling. Through data analyses, we identified a super-enhancer (Ets2-SE) that regulates Ets2 expression in the heart. Ets2-SE-deficient mice exhibited significantly lower Ets2 expression in cardiac tissues and displayed advanced aging phenotypes, including increased cardiac fibrosis and dysfunction, compared to wild-type controls. SnRNA-Seq analyses revealed a remarkable downregulation of Ets2 in endothelial cells, correlating with the activation of EndoMT. Furthermore, endothelial-specific deletion of Ets2 exacerbated aging and myocardial infarction-induced cardiac fibrosis and heart dysfunction. Mechanistic studies demonstrated that silencing ETS2 in human umbilical vein endothelial cells (HUVECs) promotes EndoMT by transcriptionally suppressing the endothelial marker gene TIE1. This transition is accompanied by endothelial cell senescence and the activation of the senescence-associated secretory phenotype (SASP), which contributes to myocardial fibrosis and cardiac aging, partially mediated by Serpine1. These findings identify Ets2 as a critical regulator of EndoMT in the context of cardiac aging.CONCLUSIONSOur findings reveal that the Ets2 super-enhancer regulates Ets2 expression in cardiac endothelial cells, modulating heart aging and EndoMT. Ets2's regulation of endothelial marker genes, especially TIE1, plays a pivotal role in mitigating EndoMT and preventing senescence in cardiac vascular endothelial cells, suggesting potential therapeutic targets for addressing cardiovascular aging.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"18 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AIMSThis study explores the efficacy of immunosuppressive regimens commonly used in heart transplantation for promoting the survival of allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) grafts in non-human primates, specifically cynomolgus monkeys.METHODS AND RESULTSBy combining methylprednisolone (MPL), calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF), we ensured adequate graft survival without acute rejection. Histological analysis showed iPSC-CM survival, vascularisation, and minimal immune rejection, despite immaturity. Reducing the immunosuppressive regimen by omitting MPL and using only CNIs and MMF resulted in graft rejection, underscoring the need for all three immunosuppressants. Genetically modified hypo-immune iPSC-CMs had poor engraftment due to increased apoptosis, unrelated to immune rejection. Additionally, abatacept in combination with tacrolimus allowed MPL discontinuation without rejection, whereas amiodarone and ivabradine effectively prevented the occurrence of post-transplant ventricular arrhythmias and reduced the incidence of sudden cardiac death.CONCLUSIONSThese findings highlight the importance of optimised immunosuppressant regimens for iPSC-CM graft survival and the potential improvements in clinical outcomes in patients with severe heart failure.TRANSLATIONAL PERSPECTIVEThis study emphasises the necessity of optimised immunosuppressive regimens for allogeneic iPSC-CM transplantation. The combination of MPL, CNIs, and MMF is essential for graft survival, whereas abatacept combined with tacrolimus enables MPL discontinuation. Furthermore, amiodarone and ivabradine effectively prevent post-transplant arrhythmias. These findings contribute to advancing the clinical application of cardiac regeneration.
{"title":"Immune regulation following allogeneic iPSC-derived cardiomyocyte transplantation in non-human primates.","authors":"Shuji Chino,Hajime Ichimura,Shugo Tohyama,Hideki Kobayashi,Takashi Shiina,Hiroki Sakai,Keiichi Fukuda,Takuro Tomita,Mitsuhiko Yamada,Ayako Tateishi,Maki Ohya,Mikiko Kobayashi,Hiroyuki Kanno,Hirohito Ishigaki,Masahiro Agata,Hidekazu Takahashi,Jian Zhao,Xiao Yang,Zouhour G Omar,Ada Caruso,Yuki Tanaka,Naoko Shiba,Yuko Wada,Tatsuichiro Seto,James J H Chong,Shin Kadota,Yuji Shiba","doi":"10.1093/cvr/cvaf249","DOIUrl":"https://doi.org/10.1093/cvr/cvaf249","url":null,"abstract":"AIMSThis study explores the efficacy of immunosuppressive regimens commonly used in heart transplantation for promoting the survival of allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) grafts in non-human primates, specifically cynomolgus monkeys.METHODS AND RESULTSBy combining methylprednisolone (MPL), calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF), we ensured adequate graft survival without acute rejection. Histological analysis showed iPSC-CM survival, vascularisation, and minimal immune rejection, despite immaturity. Reducing the immunosuppressive regimen by omitting MPL and using only CNIs and MMF resulted in graft rejection, underscoring the need for all three immunosuppressants. Genetically modified hypo-immune iPSC-CMs had poor engraftment due to increased apoptosis, unrelated to immune rejection. Additionally, abatacept in combination with tacrolimus allowed MPL discontinuation without rejection, whereas amiodarone and ivabradine effectively prevented the occurrence of post-transplant ventricular arrhythmias and reduced the incidence of sudden cardiac death.CONCLUSIONSThese findings highlight the importance of optimised immunosuppressant regimens for iPSC-CM graft survival and the potential improvements in clinical outcomes in patients with severe heart failure.TRANSLATIONAL PERSPECTIVEThis study emphasises the necessity of optimised immunosuppressive regimens for allogeneic iPSC-CM transplantation. The combination of MPL, CNIs, and MMF is essential for graft survival, whereas abatacept combined with tacrolimus enables MPL discontinuation. Furthermore, amiodarone and ivabradine effectively prevent post-transplant arrhythmias. These findings contribute to advancing the clinical application of cardiac regeneration.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"7 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
AIMSMitochondria reactive oxygen species (ROS) play a critical role in the progression of cardiac fibrosis. Nonetheless, the role of mitochondria ROS in cardiac fibroblasts cytoskeletal remodeling and ferroptosis have not been explored. However, little is known about the epigenetic mechanisms through mitochondria ROS, cytoskeletal remodeling and ferroptosis in cardiac fibrosis (CF).METHODS AND RESULTSCardiac fibroblast-specific methyl-CpG-binding protein 2 (MeCP2)-deficient mice and wild type mice were treated with Isoprenaline to induce replacement cardiac fibrosis. AAV9 carrying fibroblast-specific POSTN promoter-driven small hairpin RNA targeting superoxide dismutase 2(SOD2), and overexpression of SOD2 were administered to investigate their vital roles in cardiac fibrosis. Biochemical and histological analyses were performed to determine how MeCP2 transcriptional repression of SOD2 through mitochondria ROS, cytoskeletal remodeling and ferroptosis in cardiac fibrosis. The reconstitution of SOD2 in MeCP2-deficient cardiac fibroblasts and mouse hearts was performed to study its effect on mitochondria ROS, cytoskeletal remodeling, ferroptosis and fibrosis. Human heart tissue from patients with atrial fibrillation is used for translational validation.Downregulation of SOD2 in replacement cardiac fibrosis is associated with increased mitochondria ROS, decreased mitochondrial membrane potential (MMP), and enhanced cytoskeletal remodeling. Fibroblasts-specific SOD2 deficiency enhances mitochondrial ROS, decreases MMP, promotes cytoskeletal remodeling and fibroblasts ferroptosis, leading to cardiac fibrosis. Specifically, SOD2 downregulation is associated with elevated CpG 5mC levels. Mechanistically, methyl-CpG binding protein MeCP2 recognizes bond to SOD2 CpG 5mC and recruits H3K27me3, resulting in SOD2 transcriptional repression. MeCP2 knockdown rescues SOD2 inhibition and mitigates cytoskeletal remodeling, ferroptosis and fibrosis. In addition, human atrial fibrillation fibrotic atrial tissue exhibits signs of MeCP2 upregulation, SOD2 inhibition, elevated mitochondria ROS, and ferroptosis.CONCLUSIONSWe demonstrated a novel epigenetic mechanism through which silencing of SOD2 boosts mitochondria ROS, cytoskeletal remodeling, ferroptosis and promotes cardiac fibrosis. Our findings provide new insights for the development of preventive measures for replacement cardiac fibrosis.TRANSLATIONAL PERSPECTIVESThese results demonstrate a clinically relevant role for the MeCP2/SOD2 axis in mitigating replacement cardiac fibrosis, and targeting SOD2 5mC DNA methylation, cytoskeletal remodeling, ferroptosis may serve as a promising therapeutic strategy for treating replacement cardiac fibrosis.
{"title":"Epigenetic blockade of SOD2 boosts mitochondria ROS and cytoskeleton remodeling in cardiac fibrosis.","authors":"Yun-Sen Zhang,Zhen-Yu Liu,Li-Chan Lin,Bin Tu,Sui Mao,Kai Song,Peng Liu,Jing-Jing Yang,Qi Chen,Jian-Yuan Zhao,Hui Tao","doi":"10.1093/cvr/cvaf257","DOIUrl":"https://doi.org/10.1093/cvr/cvaf257","url":null,"abstract":"AIMSMitochondria reactive oxygen species (ROS) play a critical role in the progression of cardiac fibrosis. Nonetheless, the role of mitochondria ROS in cardiac fibroblasts cytoskeletal remodeling and ferroptosis have not been explored. However, little is known about the epigenetic mechanisms through mitochondria ROS, cytoskeletal remodeling and ferroptosis in cardiac fibrosis (CF).METHODS AND RESULTSCardiac fibroblast-specific methyl-CpG-binding protein 2 (MeCP2)-deficient mice and wild type mice were treated with Isoprenaline to induce replacement cardiac fibrosis. AAV9 carrying fibroblast-specific POSTN promoter-driven small hairpin RNA targeting superoxide dismutase 2(SOD2), and overexpression of SOD2 were administered to investigate their vital roles in cardiac fibrosis. Biochemical and histological analyses were performed to determine how MeCP2 transcriptional repression of SOD2 through mitochondria ROS, cytoskeletal remodeling and ferroptosis in cardiac fibrosis. The reconstitution of SOD2 in MeCP2-deficient cardiac fibroblasts and mouse hearts was performed to study its effect on mitochondria ROS, cytoskeletal remodeling, ferroptosis and fibrosis. Human heart tissue from patients with atrial fibrillation is used for translational validation.Downregulation of SOD2 in replacement cardiac fibrosis is associated with increased mitochondria ROS, decreased mitochondrial membrane potential (MMP), and enhanced cytoskeletal remodeling. Fibroblasts-specific SOD2 deficiency enhances mitochondrial ROS, decreases MMP, promotes cytoskeletal remodeling and fibroblasts ferroptosis, leading to cardiac fibrosis. Specifically, SOD2 downregulation is associated with elevated CpG 5mC levels. Mechanistically, methyl-CpG binding protein MeCP2 recognizes bond to SOD2 CpG 5mC and recruits H3K27me3, resulting in SOD2 transcriptional repression. MeCP2 knockdown rescues SOD2 inhibition and mitigates cytoskeletal remodeling, ferroptosis and fibrosis. In addition, human atrial fibrillation fibrotic atrial tissue exhibits signs of MeCP2 upregulation, SOD2 inhibition, elevated mitochondria ROS, and ferroptosis.CONCLUSIONSWe demonstrated a novel epigenetic mechanism through which silencing of SOD2 boosts mitochondria ROS, cytoskeletal remodeling, ferroptosis and promotes cardiac fibrosis. Our findings provide new insights for the development of preventive measures for replacement cardiac fibrosis.TRANSLATIONAL PERSPECTIVESThese results demonstrate a clinically relevant role for the MeCP2/SOD2 axis in mitigating replacement cardiac fibrosis, and targeting SOD2 5mC DNA methylation, cytoskeletal remodeling, ferroptosis may serve as a promising therapeutic strategy for treating replacement cardiac fibrosis.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"154 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ting Zhou,Huan Yang,Jooyong Kim,Carmel Assa,Elise DeRoo,Jack Bontekoe,Brian Burkel,Suzanne Ponik,Hong S Lu,Alan Daugherty,Bo Liu
AIMSAbdominal aortic aneurysms (AAA) rupture is a life-threatening event with unclear molecular mechanisms. Our previous work demonstrated elevated levels of the matricellular protein thrombospondin-1 (TSP1, encoded by Thbs1) in human and mouse AAA tissues. Single-cell RNA sequencing analysis identified macrophages, endothelial cells, and smooth muscle cells as the major TSP1-expressing cells in aneurysmal tissues. Global Thbs1 deletion reduces aneurysm formation by inhibiting vascular inflammation.The aim of this study was to investigate how TSP1 deficiency in different cell types affects AAA rupture.METHODS AND RESULTSAAA and rupture were induced by angiotensin II infusion in hypercholesterolemic mice. In global Thbs1 deficient mice, hypercholesterolemia was achieved by crossing them with Apoe knockout mice. To generate cell type-specific TSP1 deficient mice, Thbs1 flox/flox mice were crossed with VE-cadherin-Cre, SMMHC-iCreERT2, and Lyz2-Cre mice to target endothelial cells, smooth muscle cells, and myeloid cells, respectively. In these conditional knockout models, hypercholesterolemia was induced via AAV-PCSK9. We found that both global and myeloid-specific Thbs1 deletion increased rupture rate over twofold, whereas endothelial- or smooth muscle cell-specific deletion had no significant effect. Endothelial-specific Thbs1 deletion reduced aneurysm size in the CaCl₂ model. Single-cell RNA sequencing and histology in myeloid-specific Thbs1 knockout aortas revealed broad suppression of inflammation and extracellular matrix production.CONCLUSIONSMyeloid-derived TSP1 plays a critical role in inhibiting aneurysm rupture in mice, likely by promoting matrix repair phenotypes in vascular smooth muscle cells, enhancing vascular wall integrity.TRANSLATIONAL PERSPECTIVEThese findings highlight myeloid-derived TSP1 as a potential therapeutic target to prevent AAA rupture by promoting vascular wall stability and repair.
{"title":"Cell-dependent contributions of thrombospondin-1 to the rupture of abdominal aortic aneurysm in mice.","authors":"Ting Zhou,Huan Yang,Jooyong Kim,Carmel Assa,Elise DeRoo,Jack Bontekoe,Brian Burkel,Suzanne Ponik,Hong S Lu,Alan Daugherty,Bo Liu","doi":"10.1093/cvr/cvaf243","DOIUrl":"https://doi.org/10.1093/cvr/cvaf243","url":null,"abstract":"AIMSAbdominal aortic aneurysms (AAA) rupture is a life-threatening event with unclear molecular mechanisms. Our previous work demonstrated elevated levels of the matricellular protein thrombospondin-1 (TSP1, encoded by Thbs1) in human and mouse AAA tissues. Single-cell RNA sequencing analysis identified macrophages, endothelial cells, and smooth muscle cells as the major TSP1-expressing cells in aneurysmal tissues. Global Thbs1 deletion reduces aneurysm formation by inhibiting vascular inflammation.The aim of this study was to investigate how TSP1 deficiency in different cell types affects AAA rupture.METHODS AND RESULTSAAA and rupture were induced by angiotensin II infusion in hypercholesterolemic mice. In global Thbs1 deficient mice, hypercholesterolemia was achieved by crossing them with Apoe knockout mice. To generate cell type-specific TSP1 deficient mice, Thbs1 flox/flox mice were crossed with VE-cadherin-Cre, SMMHC-iCreERT2, and Lyz2-Cre mice to target endothelial cells, smooth muscle cells, and myeloid cells, respectively. In these conditional knockout models, hypercholesterolemia was induced via AAV-PCSK9. We found that both global and myeloid-specific Thbs1 deletion increased rupture rate over twofold, whereas endothelial- or smooth muscle cell-specific deletion had no significant effect. Endothelial-specific Thbs1 deletion reduced aneurysm size in the CaCl₂ model. Single-cell RNA sequencing and histology in myeloid-specific Thbs1 knockout aortas revealed broad suppression of inflammation and extracellular matrix production.CONCLUSIONSMyeloid-derived TSP1 plays a critical role in inhibiting aneurysm rupture in mice, likely by promoting matrix repair phenotypes in vascular smooth muscle cells, enhancing vascular wall integrity.TRANSLATIONAL PERSPECTIVEThese findings highlight myeloid-derived TSP1 as a potential therapeutic target to prevent AAA rupture by promoting vascular wall stability and repair.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"27 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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