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}
Ivana Jorgacevic,Haroon Shaikh,Hla Ali,Maja Bundalo,Sarah Schäfer,Michael A G Kern,Maike Büttner-Herold,Simone Reu-Hofer,Clément Cochain,Hendrik Bartolomaeus,Antoine-Emmanuel Saliba,Melanie Rösch,Giuseppe Rizzo,Estibaliz Arellano Viera,Juan Gamboa Vargas,Friederike Berberich-Siebelt,Wolfgang Herr,Louis Boon,Andreas Rosenwald,Elke Butt,Heike M Hermanns,Andreas Beilhack,Alma Zernecke
AIMSPatients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are at risk of developing graft-versus-host disease (GvHD) and are afflicted with an increased incidence of cardiovascular events. Whether allo-HCT contributes to atherosclerosis progression has not been addressed experimentally.METHODS AND RESULTSHere, we applied a novel minor histocompatibility antigen-(miHAg)-mismatch allo-HCT mouse model by transplanting C57BL/6 mice deficient for the low-density lipoprotein receptor (B6.Ldlr-/-) with bone marrow (BM) or BM and T cells (BMT) from BALB/b donors (BALB/b, H-2b → B6.Ldlr-/-, H-2b), and feeding recipients a Western diet. Mild clinical GvHD symptoms ensued with low disease activity in typical GvHD target organs. However, allogeneic BMT-recipients developed increased atherosclerotic lesions compared to mice receiving BM only or syngeneic BMT-recipients. Atherosclerotic lesions showed a heightened infiltration of effector CD8+ T cells in the aorta of BMT recipients. Furthermore, BMT recipients exhibited significantly higher serum cholesterol levels than BM recipients. Notably, CD8+ T cell depletion in B6.Ldlr-/- BMT recipients reduced atherosclerotic lesion formation and decreased cholesterol levels.CONCLUSIONSThese data may provide a novel mechanistic underpinning for the clinically observed increased incidence of cardiovascular disease in long-term allo-HCT survivors. Moreover, we have identified CD8+ T cells as potential targets for mitigating GvHD-induced atherosclerosis.
{"title":"Allogeneic hematopoietic cell transplantation initiates atherosclerosis in mice via CD8+ T cells.","authors":"Ivana Jorgacevic,Haroon Shaikh,Hla Ali,Maja Bundalo,Sarah Schäfer,Michael A G Kern,Maike Büttner-Herold,Simone Reu-Hofer,Clément Cochain,Hendrik Bartolomaeus,Antoine-Emmanuel Saliba,Melanie Rösch,Giuseppe Rizzo,Estibaliz Arellano Viera,Juan Gamboa Vargas,Friederike Berberich-Siebelt,Wolfgang Herr,Louis Boon,Andreas Rosenwald,Elke Butt,Heike M Hermanns,Andreas Beilhack,Alma Zernecke","doi":"10.1093/cvr/cvaf229","DOIUrl":"https://doi.org/10.1093/cvr/cvaf229","url":null,"abstract":"AIMSPatients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are at risk of developing graft-versus-host disease (GvHD) and are afflicted with an increased incidence of cardiovascular events. Whether allo-HCT contributes to atherosclerosis progression has not been addressed experimentally.METHODS AND RESULTSHere, we applied a novel minor histocompatibility antigen-(miHAg)-mismatch allo-HCT mouse model by transplanting C57BL/6 mice deficient for the low-density lipoprotein receptor (B6.Ldlr-/-) with bone marrow (BM) or BM and T cells (BMT) from BALB/b donors (BALB/b, H-2b → B6.Ldlr-/-, H-2b), and feeding recipients a Western diet. Mild clinical GvHD symptoms ensued with low disease activity in typical GvHD target organs. However, allogeneic BMT-recipients developed increased atherosclerotic lesions compared to mice receiving BM only or syngeneic BMT-recipients. Atherosclerotic lesions showed a heightened infiltration of effector CD8+ T cells in the aorta of BMT recipients. Furthermore, BMT recipients exhibited significantly higher serum cholesterol levels than BM recipients. Notably, CD8+ T cell depletion in B6.Ldlr-/- BMT recipients reduced atherosclerotic lesion formation and decreased cholesterol levels.CONCLUSIONSThese data may provide a novel mechanistic underpinning for the clinically observed increased incidence of cardiovascular disease in long-term allo-HCT survivors. Moreover, we have identified CD8+ T cells as potential targets for mitigating GvHD-induced atherosclerosis.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"75 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545088","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}
Georgios Krilis, Hannah M Costello, Frances Turner, Robert Little, Anastasiia Komolova, Josselin Nespoux, Alicja Czopek, Donald R Dunbar, Matthew A Bailey, Jess R Ivy
Aims Molecular clocks in the vasculature contribute to the normal circadian blood pressure (BP) rhythm. Glucocorticoids are known to synchronise molecular clocks within peripheral tissues. Disruption of the endogenous glucocorticoid rhythm causes “non-dipping”, a BP pattern associated with elevated cardiovascular risk. The mechanisms for this are unclear but vascular changes likely contribute. We examined the effect of impaired glucocorticoid rhythmicity on the time-of-day dependent vascular function and define the circadian transcriptome under control conditions and under arrhythmic glucocorticoids. Methods and Results Male C57BL6J mice kept on a 12:12 hour light/dark cycle were implanted with a subcutaneous slow-release pellet containing vehicle or corticosterone (∼3.7mg/kg/day), which flattened the endogenous glucocorticoid rhythm. After 7 days, renal arteries were isolated at 7am and 7pm to measure vasoreactivity using wire myography. Other arteries were taken 2-hourly over a 48-hour period for RNA sequencing. In control arteries, endothelium-dependent and independent vasodilation was elevated at wake-phase compared to the sleep-phase. This temporal variation was absent in the renal arteries from corticosterone treated mice. Using CircaCompare and LimoRhyde, we found circadian rhythms in 459 of the 14 225 protein-coding transcripts in control arteries. Following corticosterone treatment, circadian rhythmicity was no longer detected in 156 genes, including genes involved in “peroxide homeostasis” such as Nox4, and “TNF signalling” like Mmp14. Paradoxically 492 genes gained rhythmicity with most related to mitochondrial activity. Conclusions This study expands the molecular landscape for understanding circadian vascular physiology and emphasises the impact of glucocorticoid rhythm on temporal changes in gene expression and vascular function. This is clinically relevant to the pathogenesis of vascular dysfunction associated with perturbed glucocorticoid signalling, for example in metabolic syndrome and chronic stress.
{"title":"“Loss of circulating glucocorticoid rhythm disrupts the circadian transcriptome and vascular reactivity in the mouse renal artery.”","authors":"Georgios Krilis, Hannah M Costello, Frances Turner, Robert Little, Anastasiia Komolova, Josselin Nespoux, Alicja Czopek, Donald R Dunbar, Matthew A Bailey, Jess R Ivy","doi":"10.1093/cvr/cvaf236","DOIUrl":"https://doi.org/10.1093/cvr/cvaf236","url":null,"abstract":"Aims Molecular clocks in the vasculature contribute to the normal circadian blood pressure (BP) rhythm. Glucocorticoids are known to synchronise molecular clocks within peripheral tissues. Disruption of the endogenous glucocorticoid rhythm causes “non-dipping”, a BP pattern associated with elevated cardiovascular risk. The mechanisms for this are unclear but vascular changes likely contribute. We examined the effect of impaired glucocorticoid rhythmicity on the time-of-day dependent vascular function and define the circadian transcriptome under control conditions and under arrhythmic glucocorticoids. Methods and Results Male C57BL6J mice kept on a 12:12 hour light/dark cycle were implanted with a subcutaneous slow-release pellet containing vehicle or corticosterone (∼3.7mg/kg/day), which flattened the endogenous glucocorticoid rhythm. After 7 days, renal arteries were isolated at 7am and 7pm to measure vasoreactivity using wire myography. Other arteries were taken 2-hourly over a 48-hour period for RNA sequencing. In control arteries, endothelium-dependent and independent vasodilation was elevated at wake-phase compared to the sleep-phase. This temporal variation was absent in the renal arteries from corticosterone treated mice. Using CircaCompare and LimoRhyde, we found circadian rhythms in 459 of the 14 225 protein-coding transcripts in control arteries. Following corticosterone treatment, circadian rhythmicity was no longer detected in 156 genes, including genes involved in “peroxide homeostasis” such as Nox4, and “TNF signalling” like Mmp14. Paradoxically 492 genes gained rhythmicity with most related to mitochondrial activity. Conclusions This study expands the molecular landscape for understanding circadian vascular physiology and emphasises the impact of glucocorticoid rhythm on temporal changes in gene expression and vascular function. This is clinically relevant to the pathogenesis of vascular dysfunction associated with perturbed glucocorticoid signalling, for example in metabolic syndrome and chronic stress.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"4 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545705","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}
Shingo Matsumoto, Jawad H Butt, Kieran F Docherty, Pardeep S Jhund, William T Abraham, Akshay S Desai, Lars Kober, Jean L Rouleau, Milton Packer, Muthiah Vaduganathan, Scott D Solomon, John J V McMurray
Aims Experimental evidence suggests that adipose tissue may secrete aldosterone, and mineralocorticoid receptor antagonists (MRAs) appear to be more effective in patients with obesity. Therefore, we examined aldosterone levels according to measures of adiposity in patients with heart failure and reduced ejection fraction (HFrEF) participating in two large trials. Methods and results Aldosterone, N-terminal pro B-type natriuretic peptide (NT-proBNP), and B-type natriuretic peptide (BNP) levels were compared according to body mass index (BMI) categories: normal weight (<25.0 kg/m2), overweight (25.0–29.9 kg/m2), obesity class I (30.0–34.9 kg/m2), and obesity class II (≥35.0 kg/m2). Of the 2,201 patients not treated with an MRA, in whom aldosterone levels were measured at baseline in ATMOSPHERE and PARADIGM-HF, the mean age was 67.8 years, and 440 (20.0%) were female. Patients with higher BMI had a higher left ventricular ejection fraction but worse New York Heart Association functional class than those with normal weight. Higher BMI was associated with higher aldosterone levels but lower NT-proBNP and BNP levels (P for trend<0.001), compared to those with normal weight. This trend was also seen for other anthropometric measures. Conclusions Greater adiposity was associated with higher concentrations of aldosterone but lower levels of B-type natriuretic peptides in patients with HFrEF. Adipose tissue may influence the neurohumoral milieu in HFrEF, including the secretion of aldosterone.
{"title":"Obesity, aldosterone, and natriuretic peptide in patients with heart failure and reduced ejection fraction","authors":"Shingo Matsumoto, Jawad H Butt, Kieran F Docherty, Pardeep S Jhund, William T Abraham, Akshay S Desai, Lars Kober, Jean L Rouleau, Milton Packer, Muthiah Vaduganathan, Scott D Solomon, John J V McMurray","doi":"10.1093/cvr/cvaf235","DOIUrl":"https://doi.org/10.1093/cvr/cvaf235","url":null,"abstract":"Aims Experimental evidence suggests that adipose tissue may secrete aldosterone, and mineralocorticoid receptor antagonists (MRAs) appear to be more effective in patients with obesity. Therefore, we examined aldosterone levels according to measures of adiposity in patients with heart failure and reduced ejection fraction (HFrEF) participating in two large trials. Methods and results Aldosterone, N-terminal pro B-type natriuretic peptide (NT-proBNP), and B-type natriuretic peptide (BNP) levels were compared according to body mass index (BMI) categories: normal weight (&lt;25.0 kg/m2), overweight (25.0–29.9 kg/m2), obesity class I (30.0–34.9 kg/m2), and obesity class II (≥35.0 kg/m2). Of the 2,201 patients not treated with an MRA, in whom aldosterone levels were measured at baseline in ATMOSPHERE and PARADIGM-HF, the mean age was 67.8 years, and 440 (20.0%) were female. Patients with higher BMI had a higher left ventricular ejection fraction but worse New York Heart Association functional class than those with normal weight. Higher BMI was associated with higher aldosterone levels but lower NT-proBNP and BNP levels (P for trend&lt;0.001), compared to those with normal weight. This trend was also seen for other anthropometric measures. Conclusions Greater adiposity was associated with higher concentrations of aldosterone but lower levels of B-type natriuretic peptides in patients with HFrEF. Adipose tissue may influence the neurohumoral milieu in HFrEF, including the secretion of aldosterone.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"59 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535244","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}
Zengming Zhang, Tongbin Wu, Zeyu Chen, Danni Chen, Zhengyu Liang, Christopher Adams, Yu Gu, Mao Ye, Fhujjen Barroga, Sylvia Evans, Xiaohai Zhou, Ju Chen
Aims Activating Transcription Factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. Methods and Results We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as cardiomyocyte-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) (targeting exon 2-3 including the polyadenylation signal (polyA)) mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. Conclusions We found that the downregulation of Rps19bp1, not loss of ATF4 function, underlying the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 knockout models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.
{"title":"Transcriptional readthrough at Atf4 locus suppresses Rps19bp1 and impairs heart development","authors":"Zengming Zhang, Tongbin Wu, Zeyu Chen, Danni Chen, Zhengyu Liang, Christopher Adams, Yu Gu, Mao Ye, Fhujjen Barroga, Sylvia Evans, Xiaohai Zhou, Ju Chen","doi":"10.1093/cvr/cvaf237","DOIUrl":"https://doi.org/10.1093/cvr/cvaf237","url":null,"abstract":"Aims Activating Transcription Factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. Methods and Results We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as cardiomyocyte-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) (targeting exon 2-3 including the polyadenylation signal (polyA)) mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. Conclusions We found that the downregulation of Rps19bp1, not loss of ATF4 function, underlying the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 knockout models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"93 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535245","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}
Laura Heuvelmans, Dylan Mostert, Giulia Spanò, Monika Stoll, Leon J De Windt
Mammalian cardiac development and homeostasis rely on tightly coordinated transcriptional programs driven by core cardiogenic transcription factors. Among these, GATA binding protein 4 (GATA4) plays a pivotal role – not only in orchestrating embryonic heart formation, but also in modulating cardiac adaptation to physiological and pathological stress. To fulfil its canonical functions, emerging evidence reveals that GATA4 activity is shaped by a multilayered regulatory network involving chromatin dynamics, transcriptional and post-transcriptional inputs, and diverse post-translational modifications. In this review, we provide an integrated overview of the roles of GATA4 across developmental stages, postnatal physiology, and disease contexts. We further examine how chromatin occupancy and regulatory mechanisms fine-tune GATA4 function and evaluate current strategies that leverage GATA4 modulation for cardiac repair and regeneration. By highlighting both established and underexplored facets of GATA4 biology, this review establishes GATA4 as a central regulator of cardiac identity and plasticity, with broad implications for developmental biology, cardiac physiology, and therapeutic innovation.
{"title":"GATA4: orchestrating cardiac development and beyond","authors":"Laura Heuvelmans, Dylan Mostert, Giulia Spanò, Monika Stoll, Leon J De Windt","doi":"10.1093/cvr/cvaf230","DOIUrl":"https://doi.org/10.1093/cvr/cvaf230","url":null,"abstract":"Mammalian cardiac development and homeostasis rely on tightly coordinated transcriptional programs driven by core cardiogenic transcription factors. Among these, GATA binding protein 4 (GATA4) plays a pivotal role – not only in orchestrating embryonic heart formation, but also in modulating cardiac adaptation to physiological and pathological stress. To fulfil its canonical functions, emerging evidence reveals that GATA4 activity is shaped by a multilayered regulatory network involving chromatin dynamics, transcriptional and post-transcriptional inputs, and diverse post-translational modifications. In this review, we provide an integrated overview of the roles of GATA4 across developmental stages, postnatal physiology, and disease contexts. We further examine how chromatin occupancy and regulatory mechanisms fine-tune GATA4 function and evaluate current strategies that leverage GATA4 modulation for cardiac repair and regeneration. By highlighting both established and underexplored facets of GATA4 biology, this review establishes GATA4 as a central regulator of cardiac identity and plasticity, with broad implications for developmental biology, cardiac physiology, and therapeutic innovation.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"27 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515884","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 Pro-inflammatory macrophages are critical mediators of the viral myocarditis (VMC) pathological process. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a key enzyme involved in one-carbon metabolism, plays an essential regulatory role in macrophage function. However, the regulatory effect of MTHFD2 on macrophages in VMC remains unclear. Here, we investigated whether MTHFD2 regulates macrophage function to exert a protective effect against coxsackievirus B3 (CVB3)-induced myocarditis. Methods and results Six-week-old C57BL/6J and BALB/c mice were intraperitoneally injected with CVB3 to establish the VMC model, and blood samples from the mice were examined for targeting analysis of folate metabolism-related compounds. The myeloid cell-specific MTHFD2 knockout mice Mthfd2fl/flLyz2-Cre+ (MTHFD2-KO-Mφ) and littermate mice underwent peripheral blood proteomic analysis. We observed activation of the one-carbon metabolism folate cycle and upregulation of MTHFD2 in macrophages during myocarditis. Further, CVB3-infected MTHFD2-KO-Mφ mice exhibited higher cardiac immunocyte infiltration, especially pro-inflammatory macrophages, aggravated myocardial injury, and cardiac dysfunction. MTHFD2 knockdown also enhanced the migration of bone marrow-derived macrophages and increased their polarization toward a pro-inflammatory phenotype. Proteomic analysis identified Rap1 as a direct downstream target of MTHFD2 in VMC. Specifically, MTHFD2 modulated integrin-regulated monocyte-macrophage migration via Rap1a and reduced cellular pro-inflammatory differentiation in VMC by inhibiting Rap1/p38 MAPK signaling. Both MTHFD2 administration and high-folate diet feeding reduced cardiac inflammation and fibrosis and improved cardiac function in mice with VMC. Conclusions We identified MTHFD2 as an immune regulator of monocyte-macrophage homeostasis to protect against CVB3-induced VMC. Targeted regulation of MTHFD2 is a potential therapeutic option for VMC clinically.
目的促炎巨噬细胞是病毒性心肌炎（VMC）病理过程的重要介质。亚甲基四氢叶酸脱氢酶2 （MTHFD2）是参与单碳代谢的关键酶，在巨噬细胞功能中起着重要的调节作用。然而，MTHFD2对VMC中巨噬细胞的调节作用尚不清楚。在这里，我们研究了MTHFD2是否调节巨噬细胞功能以对柯萨奇病毒B3 （CVB3）诱导的心肌炎发挥保护作用。方法和结果6周龄C57BL/6J和BALB/c小鼠腹腔注射CVB3建立VMC模型，检测小鼠血样中叶酸代谢相关化合物的靶向性分析。骨髓细胞特异性MTHFD2敲除小鼠Mthfd2fl/flLyz2-Cre+ (MTHFD2- ko - m φ)和幼崽小鼠外周血蛋白质组学分析。我们观察到心肌炎期间巨噬细胞中单碳代谢叶酸循环的激活和MTHFD2的上调。此外，cvb3感染的MTHFD2-KO-Mφ小鼠表现出更高的心脏免疫细胞浸润，特别是促炎巨噬细胞，心肌损伤加重，心功能障碍。MTHFD2敲低也增强了骨髓源性巨噬细胞的迁移，并增加了它们向促炎表型的极化。蛋白质组学分析发现Rap1是VMC中MTHFD2的直接下游靶点。具体来说，MTHFD2通过Rap1a调节整合素调控的单核巨噬细胞迁移，并通过抑制Rap1/p38 MAPK信号传导减少VMC细胞促炎分化。MTHFD2和高叶酸饮食均可减轻VMC小鼠的心脏炎症和纤维化，并改善心功能。结论MTHFD2是单核-巨噬细胞稳态的免疫调节因子，可预防cvb3诱导的VMC。靶向调节MTHFD2是临床上治疗VMC的潜在选择。
{"title":"MTHFD2 orchestrates monocyte-macrophage immune homeostasis by targeting Rap1 to protect against CVB3-induced viral myocarditis","authors":"Fei Gao, Weidong Yu, Danxiang Feng, Xiangli Xu, Guiming Sun, Xiaoping Leng, Shuai Fu, Pingping Wan, Guoxia Shi, Yi Li, Jiawei Tian, Ping Sun","doi":"10.1093/cvr/cvaf227","DOIUrl":"https://doi.org/10.1093/cvr/cvaf227","url":null,"abstract":"Aims Pro-inflammatory macrophages are critical mediators of the viral myocarditis (VMC) pathological process. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a key enzyme involved in one-carbon metabolism, plays an essential regulatory role in macrophage function. However, the regulatory effect of MTHFD2 on macrophages in VMC remains unclear. Here, we investigated whether MTHFD2 regulates macrophage function to exert a protective effect against coxsackievirus B3 (CVB3)-induced myocarditis. Methods and results Six-week-old C57BL/6J and BALB/c mice were intraperitoneally injected with CVB3 to establish the VMC model, and blood samples from the mice were examined for targeting analysis of folate metabolism-related compounds. The myeloid cell-specific MTHFD2 knockout mice Mthfd2fl/flLyz2-Cre+ (MTHFD2-KO-Mφ) and littermate mice underwent peripheral blood proteomic analysis. We observed activation of the one-carbon metabolism folate cycle and upregulation of MTHFD2 in macrophages during myocarditis. Further, CVB3-infected MTHFD2-KO-Mφ mice exhibited higher cardiac immunocyte infiltration, especially pro-inflammatory macrophages, aggravated myocardial injury, and cardiac dysfunction. MTHFD2 knockdown also enhanced the migration of bone marrow-derived macrophages and increased their polarization toward a pro-inflammatory phenotype. Proteomic analysis identified Rap1 as a direct downstream target of MTHFD2 in VMC. Specifically, MTHFD2 modulated integrin-regulated monocyte-macrophage migration via Rap1a and reduced cellular pro-inflammatory differentiation in VMC by inhibiting Rap1/p38 MAPK signaling. Both MTHFD2 administration and high-folate diet feeding reduced cardiac inflammation and fibrosis and improved cardiac function in mice with VMC. Conclusions We identified MTHFD2 as an immune regulator of monocyte-macrophage homeostasis to protect against CVB3-induced VMC. Targeted regulation of MTHFD2 is a potential therapeutic option for VMC clinically.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"70 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484727","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}
Yahao Zhang, Tingting Xiao, Jiandong Ding, Hao Jin, Yong Wu, Orion I R Chiara Villamil, Dong Wang, Mingming Yang, Junyan Cai, Genshan Ma, Wenbin Lu
Aims Acute myocardial infarction results in significant mortality and chronic heart failure, with reperfusion frequently inducing myocardial ischemia-reperfusion (IR) injury mediated by infiltrating monocytes and monocyte-derived macrophages (iMacs). The olfactory receptor 2 (Olfr2) is hypothesized to serve as a pivotal inflammatory mediator in this context. This study aimed to elucidate the regulatory role of Olfr2 in mitochondrial homeostasis and inflammation in iMacs during myocardial IR injury. Methods and results The surface expression of OR6A2 (human ortholog of Olfr2) on monocyte subsets was assessed to determine its association with major adverse cardiovascular events (MACEs) in IR-injured patients. The mechanistic role of Olfr2 in modulating iMacs during myocardial IR injury was investigated using both in vivo and in vitro interventions targeting Olfr2. Elevated OR6A2 levels on human monocytes and octanal, an OR6A2 agonist, were significantly associated with an increased risk of MACEs and correlated with increased oxidative stress and pro-inflammatory responses in patients with IR injury. The genetic ablation of Olfr2 in mice demonstrated significant attenuation of mitochondrial reactive oxygen species (mtROS) and pro-inflammatory cytokine in iMacs, accompanied by diminished immune cell infiltration and reduced cardiomyocyte apoptosis, ultimately ameliorating myocardial IR injury. Mechanistically, Olfr2 activated nuclear receptor subfamily 4 group A member 1 (NR4A1) via cAMP/PKA signaling, promoting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which led to mitochondrial mtROS overproduction, mitochondrial membrane potential disruption, mitochondrial apoptosis, and the subsequent release of pro-inflammatory factors through NLRP3 inflammasome activation. Notably, monocyte/macrophage-specific NR4A1 overexpression in Olfr2 knockout mice negated the cardiovascular protection observed during IR injury. Conclusions Elevated OR6A2 expression and octanal levels were significantly associated with an increased risk of MACEs. Our findings identified the Olfr2/cAMP/PKA/NR4A1 axis as a novel signaling pathway contributing to cardiac IR injury by promoting Drp1-mediated mitochondrial fission and subsequent production of pro-inflammatory cytokines.
{"title":"Targeting olfactory receptor 2 on monocytes for cardioprotection against myocardial ischemia-reperfusion injury via NR4A1-mediated mitochondrial fission","authors":"Yahao Zhang, Tingting Xiao, Jiandong Ding, Hao Jin, Yong Wu, Orion I R Chiara Villamil, Dong Wang, Mingming Yang, Junyan Cai, Genshan Ma, Wenbin Lu","doi":"10.1093/cvr/cvaf232","DOIUrl":"https://doi.org/10.1093/cvr/cvaf232","url":null,"abstract":"Aims Acute myocardial infarction results in significant mortality and chronic heart failure, with reperfusion frequently inducing myocardial ischemia-reperfusion (IR) injury mediated by infiltrating monocytes and monocyte-derived macrophages (iMacs). The olfactory receptor 2 (Olfr2) is hypothesized to serve as a pivotal inflammatory mediator in this context. This study aimed to elucidate the regulatory role of Olfr2 in mitochondrial homeostasis and inflammation in iMacs during myocardial IR injury. Methods and results The surface expression of OR6A2 (human ortholog of Olfr2) on monocyte subsets was assessed to determine its association with major adverse cardiovascular events (MACEs) in IR-injured patients. The mechanistic role of Olfr2 in modulating iMacs during myocardial IR injury was investigated using both in vivo and in vitro interventions targeting Olfr2. Elevated OR6A2 levels on human monocytes and octanal, an OR6A2 agonist, were significantly associated with an increased risk of MACEs and correlated with increased oxidative stress and pro-inflammatory responses in patients with IR injury. The genetic ablation of Olfr2 in mice demonstrated significant attenuation of mitochondrial reactive oxygen species (mtROS) and pro-inflammatory cytokine in iMacs, accompanied by diminished immune cell infiltration and reduced cardiomyocyte apoptosis, ultimately ameliorating myocardial IR injury. Mechanistically, Olfr2 activated nuclear receptor subfamily 4 group A member 1 (NR4A1) via cAMP/PKA signaling, promoting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission, which led to mitochondrial mtROS overproduction, mitochondrial membrane potential disruption, mitochondrial apoptosis, and the subsequent release of pro-inflammatory factors through NLRP3 inflammasome activation. Notably, monocyte/macrophage-specific NR4A1 overexpression in Olfr2 knockout mice negated the cardiovascular protection observed during IR injury. Conclusions Elevated OR6A2 expression and octanal levels were significantly associated with an increased risk of MACEs. Our findings identified the Olfr2/cAMP/PKA/NR4A1 axis as a novel signaling pathway contributing to cardiac IR injury by promoting Drp1-mediated mitochondrial fission and subsequent production of pro-inflammatory cytokines.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"11 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498362","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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