Panagiotis Fountas,Chrysostomi Gialeli,Nicoline W Thorsen,Dianne Acoba,Jiangming Sun,Luke F Gamon,Annelie Shami,Mihaela Nitulescu,Ana Persson,Eva Bengtsson,Michael J Davies,Andreas Edsfeldt,Claudia Goettsch,Isabel Gonçalves
AIMSVascular atherosclerotic calcification is a pathological process marked by the abnormal deposition of calcium minerals in the intima. Asporin (ASPN) is a small leucine-rich proteoglycan which interacts with collagen and calcium. Due to its role in matrix mineralization, we hypothesized that ASPN might act as a regulator of vascular calcification, thereby promoting atherosclerotic plaque stability.METHODS AND RESULTSASPN protein, analyzed by ELISA, was quantified in 176 carotid endarterectomy plaques (Carotid Plaque Imaging Project cohort, including 98 patients with cerebrovascular symptoms and 78 asymptomatic patients). Plaque composition was assessed by histological, biochemical and immunological assays, along with bulk RNA sequencing, to investigate the role of ASPN in atherosclerosis. Patients donating plaques were followed up for postoperative cardiovascular events, median follow-up 6.58 years. The effect of ASPN on smooth muscle cell differentiation and matrix mineralization was investigated in vitro using human vascular smooth muscle cells overexpressing ASPN. Increased ASPN protein levels were observed in plaques from asymptomatic patients compared to patients with cerebrovascular symptoms. ASPN protein levels were positively associated with markers of plaque stability and regulation of extracellular matrix remodelling while showing an inverse relationship with calcification. Patients with high intraplaque ASPN had a lower risk for future cardiovascular events. Mechanistically, ASPN overexpression in vascular smooth muscle cells reduced matrix mineralization in vitro, supporting its potential role in plaque stabilization.CONCLUSIONASPN is a regulator of vascular calcification in atherosclerosis, promoting a plaque phenotype that is less prone to rupture. Additionally, high ASPN levels are associated with fewer future cardiovascular events.
{"title":"Elevated asporin expression in human atherosclerotic plaques promotes their stability and reduces the risk for cardiovascular events.","authors":"Panagiotis Fountas,Chrysostomi Gialeli,Nicoline W Thorsen,Dianne Acoba,Jiangming Sun,Luke F Gamon,Annelie Shami,Mihaela Nitulescu,Ana Persson,Eva Bengtsson,Michael J Davies,Andreas Edsfeldt,Claudia Goettsch,Isabel Gonçalves","doi":"10.1093/cvr/cvag015","DOIUrl":"https://doi.org/10.1093/cvr/cvag015","url":null,"abstract":"AIMSVascular atherosclerotic calcification is a pathological process marked by the abnormal deposition of calcium minerals in the intima. Asporin (ASPN) is a small leucine-rich proteoglycan which interacts with collagen and calcium. Due to its role in matrix mineralization, we hypothesized that ASPN might act as a regulator of vascular calcification, thereby promoting atherosclerotic plaque stability.METHODS AND RESULTSASPN protein, analyzed by ELISA, was quantified in 176 carotid endarterectomy plaques (Carotid Plaque Imaging Project cohort, including 98 patients with cerebrovascular symptoms and 78 asymptomatic patients). Plaque composition was assessed by histological, biochemical and immunological assays, along with bulk RNA sequencing, to investigate the role of ASPN in atherosclerosis. Patients donating plaques were followed up for postoperative cardiovascular events, median follow-up 6.58 years. The effect of ASPN on smooth muscle cell differentiation and matrix mineralization was investigated in vitro using human vascular smooth muscle cells overexpressing ASPN. Increased ASPN protein levels were observed in plaques from asymptomatic patients compared to patients with cerebrovascular symptoms. ASPN protein levels were positively associated with markers of plaque stability and regulation of extracellular matrix remodelling while showing an inverse relationship with calcification. Patients with high intraplaque ASPN had a lower risk for future cardiovascular events. Mechanistically, ASPN overexpression in vascular smooth muscle cells reduced matrix mineralization in vitro, supporting its potential role in plaque stabilization.CONCLUSIONASPN is a regulator of vascular calcification in atherosclerosis, promoting a plaque phenotype that is less prone to rupture. Additionally, high ASPN levels are associated with fewer future cardiovascular events.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"6 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005224","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}
Daniel Morales-Cano,Diana Sharysh,Julián Albarrán-Juárez,Antonio de Molina,Verónica Labrador-Cantarero,Cecilie Markvard Møller,Laura Carramolino,Jacob F Bentzon
AIMSProliferation of arterial smooth muscle cells (SMCs) and their modulation to alternative mesenchymal phenotypes is central to atherosclerotic lesion growth. It has been studied extensively in mouse models, but a detailed analysis of when and where different mesenchymal cell types accumulate in human atherosclerosis is lacking. This study mapped mesenchymal cell populations during the progression of human coronary atherosclerosis and explored their associations with disease processes in human carotid plaques.METHODS AND RESULTSMultiplex immunostaining protocols based on single-cell RNA sequencing-validated markers were established to detect SMCs, putatively SMC-derived mesenchymal cell subsets expressing osteoprotegerin or lumican, and macrophages in sections of left anterior descending arteries from forensic autopsies. The material comprised 44 arterial segments from 38 individuals, spanning normal intima, adaptive intimal thickening, pathological intimal thickening, and fibroatheroma. Parallel analysis of carotid endarterectomy samples allowed examination of mesenchymal cell involvement in fibrosis, calcification, and apoptosis. Validated machine learning-assisted cell classification was used to phenotype entire plaques at high microscopic resolution.The combined mesenchymal cell population constituted the majority of plaque cells at all plaque stages. Cells co-expressing contractile and mesenchymal cell markers were present in normal human coronary arteries, but mesenchymal cells lacking contractile protein expression became prominent only at the fibroatheroma stage, where fibroblast-like lumican-expressing cells localized preferentially around the necrotic core. The mesenchymal cell subtypes showed no preferential co-localization with areas of fibrosis or calcification; however, secreted osteoprotegerin was found bound to calcium deposits. Fibroblast-like, lumican-expressing cells accounted for 38-54% of all apoptotic cells for which a cell origin could be determined.CONCLUSIONSPutative SMC-derived mesenchymal cells without contractile protein expression expand at the fibroatheroma stage of coronary atherosclerosis. Fibroblast-like cells localize around the necrotic core region and account for many apoptotic cells in plaques, suggesting a role in necrotic core development.
{"title":"Fibroblast-like cells accumulate late in human coronary atherosclerosis contributing to necrotic core formation.","authors":"Daniel Morales-Cano,Diana Sharysh,Julián Albarrán-Juárez,Antonio de Molina,Verónica Labrador-Cantarero,Cecilie Markvard Møller,Laura Carramolino,Jacob F Bentzon","doi":"10.1093/cvr/cvag002","DOIUrl":"https://doi.org/10.1093/cvr/cvag002","url":null,"abstract":"AIMSProliferation of arterial smooth muscle cells (SMCs) and their modulation to alternative mesenchymal phenotypes is central to atherosclerotic lesion growth. It has been studied extensively in mouse models, but a detailed analysis of when and where different mesenchymal cell types accumulate in human atherosclerosis is lacking. This study mapped mesenchymal cell populations during the progression of human coronary atherosclerosis and explored their associations with disease processes in human carotid plaques.METHODS AND RESULTSMultiplex immunostaining protocols based on single-cell RNA sequencing-validated markers were established to detect SMCs, putatively SMC-derived mesenchymal cell subsets expressing osteoprotegerin or lumican, and macrophages in sections of left anterior descending arteries from forensic autopsies. The material comprised 44 arterial segments from 38 individuals, spanning normal intima, adaptive intimal thickening, pathological intimal thickening, and fibroatheroma. Parallel analysis of carotid endarterectomy samples allowed examination of mesenchymal cell involvement in fibrosis, calcification, and apoptosis. Validated machine learning-assisted cell classification was used to phenotype entire plaques at high microscopic resolution.The combined mesenchymal cell population constituted the majority of plaque cells at all plaque stages. Cells co-expressing contractile and mesenchymal cell markers were present in normal human coronary arteries, but mesenchymal cells lacking contractile protein expression became prominent only at the fibroatheroma stage, where fibroblast-like lumican-expressing cells localized preferentially around the necrotic core. The mesenchymal cell subtypes showed no preferential co-localization with areas of fibrosis or calcification; however, secreted osteoprotegerin was found bound to calcium deposits. Fibroblast-like, lumican-expressing cells accounted for 38-54% of all apoptotic cells for which a cell origin could be determined.CONCLUSIONSPutative SMC-derived mesenchymal cells without contractile protein expression expand at the fibroatheroma stage of coronary atherosclerosis. Fibroblast-like cells localize around the necrotic core region and account for many apoptotic cells in plaques, suggesting a role in necrotic core development.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"222 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994906","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}
AIMSSemaphorin 7A (SEMA7A), a membrane-anchored glycoprotein involved in immune and vascular signaling, has been implicated in cardiovascular diseases. However, its role in the development of abdominal aortic aneurysm (AAA) has not been defined. In this study, we investigated the role of SEMA7A in AAA progression and the underlying mechanisms.METHODS AND RESULTSA meta-analysis of genome-wide association studies (GWASs) identified SEMA7A as a candidate gene involved in AAA formation. Global and vascular smooth muscle cell (VSMC)-specific Sema7a knockout mice were generated and subjected to a CaPO4-induced AAA model. Compared with wild-type controls, SEMA7A-deficient mice exhibited a 28.6% reduction in aortic expansion, a finding that was recapitulated in VSMC-specific Sema7a knockout mice. RNA sequencing of CaPO4-stimulated mouse VSMCs, along with immunofluorescence staining of AAA tissues, revealed that SEMA7A deficiency supressed VSMC phenotypic switching. Further mechanistic studies demonstrated that SEMA7A promotes this switching via the integrin α5β1-mediated PDK1/SGK3/YTHDC1 signaling axis. Notably, administration of a synthetic SEMA7A-mimicking small peptide, ACP, significantly inhibited VSMC phenotypic switching and attenuated AAA progression.CONCLUSIONThis study underscores the critical role of SEMA7A in regulating VSMC phenotypic switching through a novel PDK1/SGK3/YTHDC1 axis, which contributes to AAA pathogenesis, suggesting that targeting SEMA7A is a promising therapeutic strategy for AAA prevention and treatment.
{"title":"Semaphorin 7A aggravates abdominal aortic aneurysm through PDK1/SGK3/YTHDC1 axis-mediated phenotypic switching of vascular smooth muscle cells.","authors":"Fengchan Li,Zhen Zhu,Fan Tang,Yun Du,Jiaxin Lyu,Lili Wu,Haofu Ni,Ying Wang,Lijie Ren,Qiongyu Lu,Huihui Liu,Lei Hong,Hongjie Wang,Chaojun Tang,Li Zhu","doi":"10.1093/cvr/cvag009","DOIUrl":"https://doi.org/10.1093/cvr/cvag009","url":null,"abstract":"AIMSSemaphorin 7A (SEMA7A), a membrane-anchored glycoprotein involved in immune and vascular signaling, has been implicated in cardiovascular diseases. However, its role in the development of abdominal aortic aneurysm (AAA) has not been defined. In this study, we investigated the role of SEMA7A in AAA progression and the underlying mechanisms.METHODS AND RESULTSA meta-analysis of genome-wide association studies (GWASs) identified SEMA7A as a candidate gene involved in AAA formation. Global and vascular smooth muscle cell (VSMC)-specific Sema7a knockout mice were generated and subjected to a CaPO4-induced AAA model. Compared with wild-type controls, SEMA7A-deficient mice exhibited a 28.6% reduction in aortic expansion, a finding that was recapitulated in VSMC-specific Sema7a knockout mice. RNA sequencing of CaPO4-stimulated mouse VSMCs, along with immunofluorescence staining of AAA tissues, revealed that SEMA7A deficiency supressed VSMC phenotypic switching. Further mechanistic studies demonstrated that SEMA7A promotes this switching via the integrin α5β1-mediated PDK1/SGK3/YTHDC1 signaling axis. Notably, administration of a synthetic SEMA7A-mimicking small peptide, ACP, significantly inhibited VSMC phenotypic switching and attenuated AAA progression.CONCLUSIONThis study underscores the critical role of SEMA7A in regulating VSMC phenotypic switching through a novel PDK1/SGK3/YTHDC1 axis, which contributes to AAA pathogenesis, suggesting that targeting SEMA7A is a promising therapeutic strategy for AAA prevention and treatment.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"85 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994945","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}
Carolyna Yamamoto, Kensuke Sakata, Syed Yusuf Ali, Shane Loeffler, Adityo Prakosa, Brock Tice, Eugene G Kholmovski, Natalia A Trayanova
Aims: Arrhythmogenic fibrotic substrates facilitate reentrant activity in the atria, contributing to the perpetuation of atrial fibrillation (AF). Catheter ablation may disrupt existing reentrant pathways but can also create new ones. This longitudinal study aimed to assess whether post-ablation AF recurrence is associated with incomplete elimination of native arrhythmogenic substrates or emergence of new arrhythmogenic substrates created by ablation lesions, addressing important questions in current AF management: why some patients experience recurrence post-ablation while others do not, and whether ablation lesions themselves contribute to post-ablation arrhythmogenesis.
Methods and results: Biatrial digital twins (DTs) derived from pre- and post-ablation contrast-enhanced MRI were used to evaluate the arrhythmogenic propensity of the fibrotic substrate - quantified by potential reentry-sites (PRs) and a vulnerability index (VI) reflecting reentry inducibility. Pre- and post-ablation DT pairs were generated for 11 patients who experienced AF recurrence (R-DTs) and 11 who did not (N-DTs). In total, 58 pre-ablation PRs and 32 post-ablation PRs were detected, with a nearly even distribution of PRs between the LA and RA both pre- and post-ablation. Pre-ablation VI was similar between N-DTs and R-DTs; however, post-ablation VI was significantly higher in R-DTs (P = 0.015). N-DTs exhibited a marked reduction in PRs following ablation, whereas R-DTs did not (P = 0.017). Both groups had few residual PRs from pre- to post-ablation, but R-DTs had many newly emergent PRs. In R-DTs, emergent PRs in the RA were accompanied by a post-ablation increase in RA fibrotic burden. In the LA, where lesions were delivered, all post-ablation reentries anchored around ablation-induced scar (ScAReentries). ScAReentries were significantly more inducible than those occurring within fibrotic substrate and were nearly three times more prevalent in R-DTs, accounting for the elevated post-ablation VI.
Conclusion: In DTs, emergent PRs in both atria underlie AF recurrence post-ablation, with ablation itself creating some PRs of high arrhythmogenic propensity.
{"title":"Arrhythmogenic substrates in atrial fibrillation and the role of ablation lesions: A longitudinal biatrial digital twin study.","authors":"Carolyna Yamamoto, Kensuke Sakata, Syed Yusuf Ali, Shane Loeffler, Adityo Prakosa, Brock Tice, Eugene G Kholmovski, Natalia A Trayanova","doi":"10.1093/cvr/cvag016","DOIUrl":"10.1093/cvr/cvag016","url":null,"abstract":"<p><strong>Aims: </strong>Arrhythmogenic fibrotic substrates facilitate reentrant activity in the atria, contributing to the perpetuation of atrial fibrillation (AF). Catheter ablation may disrupt existing reentrant pathways but can also create new ones. This longitudinal study aimed to assess whether post-ablation AF recurrence is associated with incomplete elimination of native arrhythmogenic substrates or emergence of new arrhythmogenic substrates created by ablation lesions, addressing important questions in current AF management: why some patients experience recurrence post-ablation while others do not, and whether ablation lesions themselves contribute to post-ablation arrhythmogenesis.</p><p><strong>Methods and results: </strong>Biatrial digital twins (DTs) derived from pre- and post-ablation contrast-enhanced MRI were used to evaluate the arrhythmogenic propensity of the fibrotic substrate - quantified by potential reentry-sites (PRs) and a vulnerability index (VI) reflecting reentry inducibility. Pre- and post-ablation DT pairs were generated for 11 patients who experienced AF recurrence (R-DTs) and 11 who did not (N-DTs). In total, 58 pre-ablation PRs and 32 post-ablation PRs were detected, with a nearly even distribution of PRs between the LA and RA both pre- and post-ablation. Pre-ablation VI was similar between N-DTs and R-DTs; however, post-ablation VI was significantly higher in R-DTs (P = 0.015). N-DTs exhibited a marked reduction in PRs following ablation, whereas R-DTs did not (P = 0.017). Both groups had few residual PRs from pre- to post-ablation, but R-DTs had many newly emergent PRs. In R-DTs, emergent PRs in the RA were accompanied by a post-ablation increase in RA fibrotic burden. In the LA, where lesions were delivered, all post-ablation reentries anchored around ablation-induced scar (ScAReentries). ScAReentries were significantly more inducible than those occurring within fibrotic substrate and were nearly three times more prevalent in R-DTs, accounting for the elevated post-ablation VI.</p><p><strong>Conclusion: </strong>In DTs, emergent PRs in both atria underlie AF recurrence post-ablation, with ablation itself creating some PRs of high arrhythmogenic propensity.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003021","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}
Brittany Weber,Christos P Kotanidis,Daniel M Huck,Stephanie A Besser,Kenneth Chan,Joanne Miao,Arthur Shiyovich,Rhanderson Cardoso,Camila Veronica Blair,Milena Petranovic,Jon Hainer,Nayruti Trivedi,Michael Garshick,Joseph F Merola,Karen Costenbader,Katherine Liao,Marcelo Di Carli,Ron Blankstein
{"title":"Inflammatory risk quantification in systemic inflammatory disease using coronary CT angiography.","authors":"Brittany Weber,Christos P Kotanidis,Daniel M Huck,Stephanie A Besser,Kenneth Chan,Joanne Miao,Arthur Shiyovich,Rhanderson Cardoso,Camila Veronica Blair,Milena Petranovic,Jon Hainer,Nayruti Trivedi,Michael Garshick,Joseph F Merola,Karen Costenbader,Katherine Liao,Marcelo Di Carli,Ron Blankstein","doi":"10.1093/cvr/cvag008","DOIUrl":"https://doi.org/10.1093/cvr/cvag008","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"268 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986507","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}
Bo-Ram Jin,Tripti Kumari,Jingu Lee,Jae-Sung Kim,Radka Bokorova,Atish Gheware,Carla Valenzuela Ripoll,Alireza Sargazi,Soi Jeong,Young-Min Hyun,Sana Saif Ur Rehman,Babak Razani,Janet S Lee,Ali Javaheri,Jaehyung Cho
AIMSSodium-glucose co-transporter 2 inhibitors are widely used to treat patients with type 2 diabetes and exhibit beneficial cardiovascular effects beyond glucose lowering. In this study, we investigated their potential to alleviate vaso-occlusive events and organ damage in sickle cell disease (SCD) mice.METHODS AND RESULTSIntravital and immunofluorescence microscopy reveal that 4-day oral administration of dapagliflozin (DAPA) or sotagliflozin (SOTA) significantly reduces neutrophil adhesion and transmigration in cremaster venules, with SOTA showing greater inhibition, and downregulates E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in cremaster venules of TNF-α-challenged SCD mice. Intriguingly, only SOTA improves mouse survival acutely. Similar inhibitory effects on neutrophil recruitment are observed in SCD mice subjected to hypoxia-reoxygenation. Flow chamber assays indicate that neither drug directly affects neutrophil or endothelial cell adhesive function. In addition, treatment of neutrophils and platelets from SCD mice and patients with DAPA or SOTA does not affect their activation. When administered for 4 months, DAPA or SOTA mitigates neutrophil recruitment and enhances microcirculation in cremaster venules of TNF-α-challenged SCD mice, while only SOTA confers a survival benefit. Both drugs reduce leukocyte infiltration in the liver or lungs, suggesting their ability to protect against organ damage. Co-administration with hydroxyurea for 4 months does not enhance these effects. Multiplex analysis shows that DAPA and SOTA lower plasma levels of soluble P-selectin, ICAM-1, S100A8/A9, and pro-inflammatory cytokines in SCD mice.CONCLUSIONSOur findings suggest that DAPA and SOTA mitigate vaso-occlusive events in SCD, with SOTA providing superior benefits.TRANSLATIONAL PERSPECTIVESickle cell disease (SCD) is an inherited autosomal recessive disorder characterized by red blood cell hymolysis, oxidative stress, and chronic inflammation. Recurrent vaso-occlusive crises driven by intravascular cell-cell adhesion and aggregation and the hallmark of SCD. In this study, we show that dapagliflozing (DAPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), and sotagliflozin (SOTA), an SGLT1/2i, reduce acute vaso-occlusion in SCD mice subjected to severe inflammation or hypoxia-reoxygenation, with SOTA providing greater benefit.These findings suggest that SGLT2 or SGLT1/2 inhibition may help attenuate vaso-occlusive pain crises in SCD patients.
{"title":"Beneficial effects of SGLT1/2 and SGLT2 inhibitors on vaso-occlusive events and organ damage in sickle cell disease mice.","authors":"Bo-Ram Jin,Tripti Kumari,Jingu Lee,Jae-Sung Kim,Radka Bokorova,Atish Gheware,Carla Valenzuela Ripoll,Alireza Sargazi,Soi Jeong,Young-Min Hyun,Sana Saif Ur Rehman,Babak Razani,Janet S Lee,Ali Javaheri,Jaehyung Cho","doi":"10.1093/cvr/cvag003","DOIUrl":"https://doi.org/10.1093/cvr/cvag003","url":null,"abstract":"AIMSSodium-glucose co-transporter 2 inhibitors are widely used to treat patients with type 2 diabetes and exhibit beneficial cardiovascular effects beyond glucose lowering. In this study, we investigated their potential to alleviate vaso-occlusive events and organ damage in sickle cell disease (SCD) mice.METHODS AND RESULTSIntravital and immunofluorescence microscopy reveal that 4-day oral administration of dapagliflozin (DAPA) or sotagliflozin (SOTA) significantly reduces neutrophil adhesion and transmigration in cremaster venules, with SOTA showing greater inhibition, and downregulates E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in cremaster venules of TNF-α-challenged SCD mice. Intriguingly, only SOTA improves mouse survival acutely. Similar inhibitory effects on neutrophil recruitment are observed in SCD mice subjected to hypoxia-reoxygenation. Flow chamber assays indicate that neither drug directly affects neutrophil or endothelial cell adhesive function. In addition, treatment of neutrophils and platelets from SCD mice and patients with DAPA or SOTA does not affect their activation. When administered for 4 months, DAPA or SOTA mitigates neutrophil recruitment and enhances microcirculation in cremaster venules of TNF-α-challenged SCD mice, while only SOTA confers a survival benefit. Both drugs reduce leukocyte infiltration in the liver or lungs, suggesting their ability to protect against organ damage. Co-administration with hydroxyurea for 4 months does not enhance these effects. Multiplex analysis shows that DAPA and SOTA lower plasma levels of soluble P-selectin, ICAM-1, S100A8/A9, and pro-inflammatory cytokines in SCD mice.CONCLUSIONSOur findings suggest that DAPA and SOTA mitigate vaso-occlusive events in SCD, with SOTA providing superior benefits.TRANSLATIONAL PERSPECTIVESickle cell disease (SCD) is an inherited autosomal recessive disorder characterized by red blood cell hymolysis, oxidative stress, and chronic inflammation. Recurrent vaso-occlusive crises driven by intravascular cell-cell adhesion and aggregation and the hallmark of SCD. In this study, we show that dapagliflozing (DAPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), and sotagliflozin (SOTA), an SGLT1/2i, reduce acute vaso-occlusion in SCD mice subjected to severe inflammation or hypoxia-reoxygenation, with SOTA providing greater benefit.These findings suggest that SGLT2 or SGLT1/2 inhibition may help attenuate vaso-occlusive pain crises in SCD patients.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"16 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961455","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}
Aim Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in an ageing society. Macrophages play a central role in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion; however, the role of these morphological changes, particularly in macrophages, remains unknown. This study investigated the role of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, in macrophages and its involvement in the mechanisms of left ventricular remodeling after myocardial infarction (MI). Methods and Results This study utilized genetically altered mice lacking Drp1 in Lysozyme M-positive cells (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Deletion of Drp1 in macrophages exacerbated LV remodeling, underpinned by reduced ejection fraction and increased LV diameter, which resulted in a poor prognosis after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in the infarcted hearts of Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) into the cytosol and the induction of inflammatory cytokines. This induction was abrogated by the autophagy inducer Tat-beclin1 or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by the Drp1 inhibitor Mdivi-1. Conclusion Macrophage Drp1 plays a critical role in the pathobiology of post-infarct LV remodeling, particularly in mitochondrial quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.
{"title":"Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated inflammation and inhibits post-infarct cardiac remodeling","authors":"Yuki Kondo, Jun-ichiro Koga, Nasanbadrakh Orkhonselenge, Lixiang Wang, Nao Hasuzawa, Shunsuke Katsuki, Tetsuya Matoba, Yosuke Nishimura, Masatoshi Nomura, Masaharu Kataoka","doi":"10.1093/cvr/cvag006","DOIUrl":"https://doi.org/10.1093/cvr/cvag006","url":null,"abstract":"Aim Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in an ageing society. Macrophages play a central role in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion; however, the role of these morphological changes, particularly in macrophages, remains unknown. This study investigated the role of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, in macrophages and its involvement in the mechanisms of left ventricular remodeling after myocardial infarction (MI). Methods and Results This study utilized genetically altered mice lacking Drp1 in Lysozyme M-positive cells (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Deletion of Drp1 in macrophages exacerbated LV remodeling, underpinned by reduced ejection fraction and increased LV diameter, which resulted in a poor prognosis after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in the infarcted hearts of Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) into the cytosol and the induction of inflammatory cytokines. This induction was abrogated by the autophagy inducer Tat-beclin1 or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by the Drp1 inhibitor Mdivi-1. Conclusion Macrophage Drp1 plays a critical role in the pathobiology of post-infarct LV remodeling, particularly in mitochondrial quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"29 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986321","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}
Yingxi Li,Razoan Al Rimon,Faqi Wang,Haoyang Li,Slava Epelman,Michelle D Tallquist,Lindsey Westover,Gavin Y Oudit,Zamaneh Kassiri
AIMSMyocardial infarction (MI) triggers a complex remodeling that, if uncontrolled, leads to heart failure. Increased levels of ADAM17 (disintegrin and metalloproteinase-17) in ischemic injury has been reported, but its direct role in scar formation and subsequent recovery from MI has not been identified. We investigated the role of ADAM17 in the function of homeostatic fibroblasts (FBs) vs. activated myofibroblasts (myoFBs) in scar formation, and recovery following MI.METHODS AND RESULTSHuman myocardial specimens showed upregulated ADAM17 in the infarct tissue, colocalized to myofibroblasts. We generated two inducible genetic mouse models with Adam17 knockdown in FBs (Adam17FB-KD) or myoFB (Adam17myoFB-KD) and subjected them to MI. Loss of ADAM17 in FBs impaired infarct formation and increased mortality due to left ventricular (LV) rupture in males and females. In contrast, ADAM17 loss in myoFBs limited infarct expansion, LV dilation and dysfunction up to 4-wks post-MI. Macrophage infiltration was suppressed in both genotypes. Ex vivo and in vitro experiments revealed that loss of ADAM17 in myoFB resulted in scar tissue with reduced stiffness due to suppressed activation of epidermal growth factor receptor and the Yes-associated protein (YAP) pathway. This promoted VEGFR signaling, endothelial cell (EC) proliferation, and vascularization in the infarcted myocardium, limiting infarct expansion. RNAseq analyses showed drastic changes in extracellular matrix (ECM) genes in Adam17KD FB and myoFBs in hypoxia. In vitro co-culture of myoFB and ECs confirmed that the ECM deposited by Adam17-deficient myoFB promotes EC proliferation and sprouting. Pharmacological inhibition of ADAM17 before MI was ineffective, but short-term ADAM17 inhibition after MI (targeting the myoFBs), limited infarct expansion, LV dilation and dysfunction up to 4-weeks post-MI.CONCLUSIONShort-term inhibition of ADAM17 after MI optimizes the compliance of the infarct tissue, promoting vascularization, limiting infarct expansion, preventing long-term adverse LV remodeling, dysfunction, and heart failure. Targeting the homeostatic FB vs. myoFB also highlights the critical timing of ADAM17 inhibition as its presence is essential for the initial healing of the infarcted heart, but inhibition of its persistent upregulation reduces scar stiffness and improves the outcome post-MI.
{"title":"Temporal inhibition of ADAM17 in fibroblasts reduces stiffness and promotes vascularization following myocardial infarction.","authors":"Yingxi Li,Razoan Al Rimon,Faqi Wang,Haoyang Li,Slava Epelman,Michelle D Tallquist,Lindsey Westover,Gavin Y Oudit,Zamaneh Kassiri","doi":"10.1093/cvr/cvaf256","DOIUrl":"https://doi.org/10.1093/cvr/cvaf256","url":null,"abstract":"AIMSMyocardial infarction (MI) triggers a complex remodeling that, if uncontrolled, leads to heart failure. Increased levels of ADAM17 (disintegrin and metalloproteinase-17) in ischemic injury has been reported, but its direct role in scar formation and subsequent recovery from MI has not been identified. We investigated the role of ADAM17 in the function of homeostatic fibroblasts (FBs) vs. activated myofibroblasts (myoFBs) in scar formation, and recovery following MI.METHODS AND RESULTSHuman myocardial specimens showed upregulated ADAM17 in the infarct tissue, colocalized to myofibroblasts. We generated two inducible genetic mouse models with Adam17 knockdown in FBs (Adam17FB-KD) or myoFB (Adam17myoFB-KD) and subjected them to MI. Loss of ADAM17 in FBs impaired infarct formation and increased mortality due to left ventricular (LV) rupture in males and females. In contrast, ADAM17 loss in myoFBs limited infarct expansion, LV dilation and dysfunction up to 4-wks post-MI. Macrophage infiltration was suppressed in both genotypes. Ex vivo and in vitro experiments revealed that loss of ADAM17 in myoFB resulted in scar tissue with reduced stiffness due to suppressed activation of epidermal growth factor receptor and the Yes-associated protein (YAP) pathway. This promoted VEGFR signaling, endothelial cell (EC) proliferation, and vascularization in the infarcted myocardium, limiting infarct expansion. RNAseq analyses showed drastic changes in extracellular matrix (ECM) genes in Adam17KD FB and myoFBs in hypoxia. In vitro co-culture of myoFB and ECs confirmed that the ECM deposited by Adam17-deficient myoFB promotes EC proliferation and sprouting. Pharmacological inhibition of ADAM17 before MI was ineffective, but short-term ADAM17 inhibition after MI (targeting the myoFBs), limited infarct expansion, LV dilation and dysfunction up to 4-weeks post-MI.CONCLUSIONShort-term inhibition of ADAM17 after MI optimizes the compliance of the infarct tissue, promoting vascularization, limiting infarct expansion, preventing long-term adverse LV remodeling, dysfunction, and heart failure. Targeting the homeostatic FB vs. myoFB also highlights the critical timing of ADAM17 inhibition as its presence is essential for the initial healing of the infarcted heart, but inhibition of its persistent upregulation reduces scar stiffness and improves the outcome post-MI.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"21 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949714","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：