Bryce R Evans,Julia Schulz,Vasiliki Triantafyllidou,Anais Yerly,Manovriti Thakur,Nico Angliker,Mark Siegrist,Yvonne Jansen,Yi Yan,Sanne L Maas,Christoph Gold,Floriana M Farina,Batoul Bayer,Alexander Bartelt,Christian Weber,Justus Wettich,Lars Maegdefessel,Nadia Sachs,Marc Schindewolf,Drosos Kotelis,Heidi Noels,Donato Santovito,Emiel P C van der Vorst,Yvonne Döring
OBJECTIVEHematopoietic ChemR23 deficiency was shown to reduce atherosclerotic lesions by increasing M2 macrophages, but conflicting results in systemically deficient mice suggest a cell-specific function of ChemR23. Therefore, we aimed to study the role of ChemR23 particularly on vascular smooth muscle cells (VSMCs) in atherosclerosis.METHODS AND RESULTSMice with a non-hematopoietic cell ChemR23 deficiency due to bone marrow transplantation of Apolipoprotein E deficient bone marrow into irradiated ChemR23e/e Apoe-/- double deficient recipient mice (Apoe-/- ►ChemR23e/e Apoe-/-) were fed a Western Diet for 6- or 12-weeks. Subsequent analysis revealed an increased lesion size and enhanced VSMC proliferation and VSMC foam cells in Apoe-/- ►ChemR23e/e Apoe-/-mice. Bulk RNA sequencing of adventitia-stripped aortas of Apoe-/- ►ChemR23e/e Apoe-/-mice exposed an increase in gene expression of synthetic VSMC markers such as Lgals3 and Cd68, while contractile genes were downregulated. Likewise, single-cell transcriptome data from advanced human atherosclerotic plaques uncovered the highest ChemR23 expression in contractile VSMCs while its expression in synthetic VSMCs was markedly reduced. In vitro, treatment of human aortic smooth muscle cells (HASMCs) with α-NETA, a small molecule inhibitor of ChemR23, increased synthetic gene expression but downregulated expression of TGFB, ABCA1, ABCG1 and SRB1. Further, α-NETA-treated HASMCs downregulated TGFB secretion, increased cholesterol uptake but decreased cholesterol efflux, and showed enhanced cell proliferation. Agonizing ChemR23 with its bona fide ligand chemerin 9 (C9) had no effect on synthetic gene expression but mitigated the effects of α-NETA on gene expression, cholesterol uptake, efflux, and cell proliferation. In vivo, both α-NETA and C9 treatment of Apoe-/- mice over 4 weeks WD revealed therapeutic potential. C9 reduced general inflammatory burden while α-NETA promoted an atheroprotective M2 macrophage phenotype.CONCLUSIONSThese findings suggest a critical role of ChemR23 in regulating VSMC phenotype switching thereby affecting atherosclerosis and suggest ChemR23 as a therapeutic target to either modulate inflammation (C9) or macrophage polarization (α-NETA) in atherosclerotic disease.
研究表明，造血化学r23缺乏通过增加M2巨噬细胞来减少动脉粥样硬化病变，但在系统性缺陷小鼠中，相互矛盾的结果表明，化学r23具有细胞特异性功能。因此，我们旨在研究ChemR23在动脉粥样硬化中对血管平滑肌细胞（VSMCs）的作用。方法与结果将载脂蛋白E缺乏的骨髓移植至经放射治疗的ChemR23e/ E Apoe-/-双缺陷受体小鼠（Apoe-/-►ChemR23e/ E Apoe-/-），造成非造血细胞ChemR23缺乏，饲喂西式饮食6周或12周。随后的分析显示Apoe-/- ChemR23e/e Apoe-/-小鼠的病变大小增加，VSMC增殖和VSMC泡沫细胞增强。对Apoe-/- ChemR23e/e小鼠体外剥离主动脉的大量RNA测序显示，合成VSMC标记物Lgals3和Cd68的基因表达增加，而收缩基因表达下调。同样，来自晚期人类动脉粥样硬化斑块的单细胞转录组数据显示，ChemR23在收缩性VSMCs中的表达最高，而在合成VSMCs中的表达明显降低。在体外，用ChemR23小分子抑制剂α-NETA处理人主动脉平滑肌细胞（HASMCs），可提高合成基因的表达，但下调TGFB、ABCA1、ABCG1和SRB1的表达。此外，α- neta处理的HASMCs下调TGFB分泌，增加胆固醇摄取但减少胆固醇外排，并表现出细胞增殖增强。用真正的配体趋化素9 （chemerin 9, C9）致痛ChemR23对合成基因表达没有影响，但减轻了α-NETA对基因表达、胆固醇摄取、外排和细胞增殖的影响。在体内，α-NETA和C9治疗Apoe-/-小鼠4周WD均显示出治疗潜力。C9减轻一般炎症负担，而α-NETA促进动脉粥样硬化保护M2巨噬细胞表型。这些发现表明ChemR23在调节VSMC表型转换从而影响动脉粥样硬化中起关键作用，并提示ChemR23可作为动脉粥样硬化疾病中调节炎症（C9）或巨噬细胞极化（α-NETA）的治疗靶点。
{"title":"ChemR23 prevents phenotypic switching of vascular smooth muscle cells into macrophage like foam cells in atherosclerosis.","authors":"Bryce R Evans,Julia Schulz,Vasiliki Triantafyllidou,Anais Yerly,Manovriti Thakur,Nico Angliker,Mark Siegrist,Yvonne Jansen,Yi Yan,Sanne L Maas,Christoph Gold,Floriana M Farina,Batoul Bayer,Alexander Bartelt,Christian Weber,Justus Wettich,Lars Maegdefessel,Nadia Sachs,Marc Schindewolf,Drosos Kotelis,Heidi Noels,Donato Santovito,Emiel P C van der Vorst,Yvonne Döring","doi":"10.1093/cvr/cvaf258","DOIUrl":"https://doi.org/10.1093/cvr/cvaf258","url":null,"abstract":"OBJECTIVEHematopoietic ChemR23 deficiency was shown to reduce atherosclerotic lesions by increasing M2 macrophages, but conflicting results in systemically deficient mice suggest a cell-specific function of ChemR23. Therefore, we aimed to study the role of ChemR23 particularly on vascular smooth muscle cells (VSMCs) in atherosclerosis.METHODS AND RESULTSMice with a non-hematopoietic cell ChemR23 deficiency due to bone marrow transplantation of Apolipoprotein E deficient bone marrow into irradiated ChemR23e/e Apoe-/- double deficient recipient mice (Apoe-/- ►ChemR23e/e Apoe-/-) were fed a Western Diet for 6- or 12-weeks. Subsequent analysis revealed an increased lesion size and enhanced VSMC proliferation and VSMC foam cells in Apoe-/- ►ChemR23e/e Apoe-/-mice. Bulk RNA sequencing of adventitia-stripped aortas of Apoe-/- ►ChemR23e/e Apoe-/-mice exposed an increase in gene expression of synthetic VSMC markers such as Lgals3 and Cd68, while contractile genes were downregulated. Likewise, single-cell transcriptome data from advanced human atherosclerotic plaques uncovered the highest ChemR23 expression in contractile VSMCs while its expression in synthetic VSMCs was markedly reduced. In vitro, treatment of human aortic smooth muscle cells (HASMCs) with α-NETA, a small molecule inhibitor of ChemR23, increased synthetic gene expression but downregulated expression of TGFB, ABCA1, ABCG1 and SRB1. Further, α-NETA-treated HASMCs downregulated TGFB secretion, increased cholesterol uptake but decreased cholesterol efflux, and showed enhanced cell proliferation. Agonizing ChemR23 with its bona fide ligand chemerin 9 (C9) had no effect on synthetic gene expression but mitigated the effects of α-NETA on gene expression, cholesterol uptake, efflux, and cell proliferation. In vivo, both α-NETA and C9 treatment of Apoe-/- mice over 4 weeks WD revealed therapeutic potential. C9 reduced general inflammatory burden while α-NETA promoted an atheroprotective M2 macrophage phenotype.CONCLUSIONSThese findings suggest a critical role of ChemR23 in regulating VSMC phenotype switching thereby affecting atherosclerosis and suggest ChemR23 as a therapeutic target to either modulate inflammation (C9) or macrophage polarization (α-NETA) in atherosclerotic disease.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"28 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559040","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}
Single-cell RNA sequencing has revolutionized the study of calcified aortic valve disease (CAVD) by enabling the dissection of cellular heterogeneity, lineage differentiation, and intercellular crosstalk at an unprecedented resolution. It revealed original vistas into the mechanisms of CAVD and novel putative therapeutic targets. This review provides a narrative state-of-the-art overview of single-cell RNA sequencing applications in CAVD research, summarizing key findings on valvular cell populations, disease-associated phenotypic transitions, and molecular pathways driving pathological remodeling. Additionally, the translational potential of single-cell technologies in identifying novel therapeutic targets is discussed, as well as the current challenges and future directions in this rapidly evolving field.
{"title":"Advances in single-cell transcriptomics: unraveling the pathogenesis of calcific aortic valve disease.","authors":"Zihan Qin,Magnus Bäck","doi":"10.1093/cvr/cvaf255","DOIUrl":"https://doi.org/10.1093/cvr/cvaf255","url":null,"abstract":"Single-cell RNA sequencing has revolutionized the study of calcified aortic valve disease (CAVD) by enabling the dissection of cellular heterogeneity, lineage differentiation, and intercellular crosstalk at an unprecedented resolution. It revealed original vistas into the mechanisms of CAVD and novel putative therapeutic targets. This review provides a narrative state-of-the-art overview of single-cell RNA sequencing applications in CAVD research, summarizing key findings on valvular cell populations, disease-associated phenotypic transitions, and molecular pathways driving pathological remodeling. Additionally, the translational potential of single-cell technologies in identifying novel therapeutic targets is discussed, as well as the current challenges and future directions in this rapidly evolving field.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"2 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559041","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}
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}
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