Pub Date : 2025-08-26DOI: 10.1038/s44161-025-00700-7
Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis
Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns. Zhang et al. show that genetically simulated IL-6 inhibition is associated with a reduced risk of cardiovascular disease and no increase in infection risk, supporting the use of emerging pharmacological treatments targeting IL-6 rather than its receptor.
{"title":"IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk","authors":"Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis","doi":"10.1038/s44161-025-00700-7","DOIUrl":"10.1038/s44161-025-00700-7","url":null,"abstract":"Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns. Zhang et al. show that genetically simulated IL-6 inhibition is associated with a reduced risk of cardiovascular disease and no increase in infection risk, supporting the use of emerging pharmacological treatments targeting IL-6 rather than its receptor.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1172-1186"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1038/s44161-025-00692-4
Milagros C. Romay, Feiyang Ma, Ana Mompeón, Michele Silvestro, Gloria E. Hernandez, Jocelynda Salvador, Andrew L. Wang, Marie Vandestienne, Nathalie Bardin, Marcel Blot-Chabaud, Aurelie S. Leroyer, Hafid Ait-Oufella, Bhama Ramkhelawon, M. Luisa Iruela-Arispe
Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. Here we perform single-cell transcriptomics in the carotids, the aortic arch and the thoracic and abdominal aorta to identify site- and sex-specific differences that could inform about vulnerability. Our findings revealed (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins and (3) differential contributions of sex-specific effectors. Furthermore, cross-referencing regional-specific signatures with available genome-wide association study and expression quantitative trait loci databases identified 339 disease candidates associated with aorta distensibility, stiffness index and blood pressure. CPNE8 and SORBS2 were further evaluated and highlighted as strong causal candidates. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM (CD146), a transcript with sex-skewed expression and lower in male mice and men, had significantly reduced expression in human aortic aneurysms. The findings reveal underlying diversity within vascular smooth muscle cell populations relevant to understanding site-specific and sex-specific variation of vascular pathologies. Single-cell profiling reveals regional and sex-specific transcriptional programs in the aorta, uncovering molecular diversity that may drive site-selective and sex-biased vulnerability to aneurysms.
{"title":"Region-specific gene expression and sex inform about disease susceptibility in the aorta","authors":"Milagros C. Romay, Feiyang Ma, Ana Mompeón, Michele Silvestro, Gloria E. Hernandez, Jocelynda Salvador, Andrew L. Wang, Marie Vandestienne, Nathalie Bardin, Marcel Blot-Chabaud, Aurelie S. Leroyer, Hafid Ait-Oufella, Bhama Ramkhelawon, M. Luisa Iruela-Arispe","doi":"10.1038/s44161-025-00692-4","DOIUrl":"10.1038/s44161-025-00692-4","url":null,"abstract":"Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. Here we perform single-cell transcriptomics in the carotids, the aortic arch and the thoracic and abdominal aorta to identify site- and sex-specific differences that could inform about vulnerability. Our findings revealed (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins and (3) differential contributions of sex-specific effectors. Furthermore, cross-referencing regional-specific signatures with available genome-wide association study and expression quantitative trait loci databases identified 339 disease candidates associated with aorta distensibility, stiffness index and blood pressure. CPNE8 and SORBS2 were further evaluated and highlighted as strong causal candidates. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM (CD146), a transcript with sex-skewed expression and lower in male mice and men, had significantly reduced expression in human aortic aneurysms. The findings reveal underlying diversity within vascular smooth muscle cell populations relevant to understanding site-specific and sex-specific variation of vascular pathologies. Single-cell profiling reveals regional and sex-specific transcriptional programs in the aorta, uncovering molecular diversity that may drive site-selective and sex-biased vulnerability to aneurysms.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1152-1171"},"PeriodicalIF":10.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1038/s44161-025-00708-z
Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang
{"title":"Publisher Correction: Tetraspanin-enriched membrane domains regulate vascular leakage by altering membrane cholesterol accessibility to balance antagonistic GTPases","authors":"Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang","doi":"10.1038/s44161-025-00708-z","DOIUrl":"10.1038/s44161-025-00708-z","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1207-1207"},"PeriodicalIF":10.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00708-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia. Watanabe et al. show that cytopathic hypoxia, through upregulation of COX2 and secretory PLA2, stabilizes HIF-1α, contributing to impaired mitochondrial respiration and reduced cardiac contraction in septic cardiomyopathy.
{"title":"Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia","authors":"Masatsugu Watanabe, Masataka Ikeda, Ko Abe, Shun Furusawa, Kosei Ishimaru, Takuya Kanamura, Satoshi Fujita, Hiroko Deguchi Miyamoto, Eisho Kozakura, Yoko Shojima Isayama, Yuki Ikeda, Takashi Kai, Toru Hashimoto, Shouji Matsushima, Tomomi Ide, Ken-ichi Yamada, Hiroyuki Tsutsui, Ken Yamaura, Kohtaro Abe","doi":"10.1038/s44161-025-00687-1","DOIUrl":"10.1038/s44161-025-00687-1","url":null,"abstract":"Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia. Watanabe et al. show that cytopathic hypoxia, through upregulation of COX2 and secretory PLA2, stabilizes HIF-1α, contributing to impaired mitochondrial respiration and reduced cardiac contraction in septic cardiomyopathy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1077-1093"},"PeriodicalIF":10.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1038/s44161-025-00680-8
Gizem Kayki Mutlu, Walter J. Koch
Septic cardiomyopathy arises from complex molecular dysfunctions including cytopathic hypoxia that impair cardiac performance. Research shows that LPS-induced phospholipid metabolism stabilizes HIF-1α in cardiomyocytes, suppressing mitochondrial function and contractility, and identifies promising targets for sepsis-related cardiac dysfunction.
{"title":"Linking phospholipid metabolism to septic cardiomyopathy via HIF-1α overactivation","authors":"Gizem Kayki Mutlu, Walter J. Koch","doi":"10.1038/s44161-025-00680-8","DOIUrl":"10.1038/s44161-025-00680-8","url":null,"abstract":"Septic cardiomyopathy arises from complex molecular dysfunctions including cytopathic hypoxia that impair cardiac performance. Research shows that LPS-induced phospholipid metabolism stabilizes HIF-1α in cardiomyocytes, suppressing mitochondrial function and contractility, and identifies promising targets for sepsis-related cardiac dysfunction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1036-1037"},"PeriodicalIF":10.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-12DOI: 10.1038/s44161-025-00701-6
Daniel J. Blackwell, Björn C. Knollmann
Ryanodine receptor (RyR2) phosphorylation was thought to regulate cardiac calcium handling and contractility. Research now shows that preventing RyR2 phosphorylation has no effect on heart rate or contractile function in response to catecholamines and instead drives an electrogenic process that can trigger lethal arrhythmia.
{"title":"Finding the right balance of RyR2 phosphorylation for arrhythmia prevention","authors":"Daniel J. Blackwell, Björn C. Knollmann","doi":"10.1038/s44161-025-00701-6","DOIUrl":"10.1038/s44161-025-00701-6","url":null,"abstract":"Ryanodine receptor (RyR2) phosphorylation was thought to regulate cardiac calcium handling and contractility. Research now shows that preventing RyR2 phosphorylation has no effect on heart rate or contractile function in response to catecholamines and instead drives an electrogenic process that can trigger lethal arrhythmia.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"962-963"},"PeriodicalIF":10.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-12DOI: 10.1038/s44161-025-00693-3
Jingjing Zheng, Daniela Ponce-Balbuena, Erick B. Ríos Pérez, Li Xiao, Holly C. Dooge, Héctor H. Valdivia, Francisco J. Alvarado
Phosphorylation of specific sites in ryanodine receptor 2 (RyR2), a major cardiac Ca2+ channel, increases channel activity and promotes pathological sarcoplasmic reticulum Ca2+ leak and arrhythmia. RyR2 is phosphorylated during adrenergic stimulation, but the role of this phosphorylation remains debated. In this study, we generated a mouse model with phospho-ablation of the three canonical phosphorylation sites in RyR2 (S2031A/S2808A/S2814A, triple phospho-mutant (TPM)) to determine their role in the adrenergic response. TPM mice have normal basal cardiac structure and function. Isoproterenol stimulation produced normal chronotropic and inotropic responses in TPM mice and cardiomyocytes, which also showed reduced RyR2-mediated Ca2+ leak. However, TPM mice were susceptible to cardiac arrhythmias. These arrhythmias required systolic Ca2+ release and were induced by the reactivation of INa and early afterdepolarizations. We propose that phosphorylation of these residues in RyR2 is dispensable for chronotropy and inotropy; however, they maintain electrical stability during adrenergic stimulation by modulating a physiological RyR2-mediated Ca2+ leak. Zheng et al. generated a mouse model of phospho-ablation in all canonical ryanodine receptor 2 (RyR2) phosphorylation sites. They show that RyR2 phosphorylation at these sites is dispensable for chronotropy and inotropy but is required to maintain electrical stability during adrenergic stimulation.
{"title":"Preventing the phosphorylation of RyR2 at canonical sites reduces Ca2+ leak and promotes arrhythmia by reactivating the INa current","authors":"Jingjing Zheng, Daniela Ponce-Balbuena, Erick B. Ríos Pérez, Li Xiao, Holly C. Dooge, Héctor H. Valdivia, Francisco J. Alvarado","doi":"10.1038/s44161-025-00693-3","DOIUrl":"10.1038/s44161-025-00693-3","url":null,"abstract":"Phosphorylation of specific sites in ryanodine receptor 2 (RyR2), a major cardiac Ca2+ channel, increases channel activity and promotes pathological sarcoplasmic reticulum Ca2+ leak and arrhythmia. RyR2 is phosphorylated during adrenergic stimulation, but the role of this phosphorylation remains debated. In this study, we generated a mouse model with phospho-ablation of the three canonical phosphorylation sites in RyR2 (S2031A/S2808A/S2814A, triple phospho-mutant (TPM)) to determine their role in the adrenergic response. TPM mice have normal basal cardiac structure and function. Isoproterenol stimulation produced normal chronotropic and inotropic responses in TPM mice and cardiomyocytes, which also showed reduced RyR2-mediated Ca2+ leak. However, TPM mice were susceptible to cardiac arrhythmias. These arrhythmias required systolic Ca2+ release and were induced by the reactivation of INa and early afterdepolarizations. We propose that phosphorylation of these residues in RyR2 is dispensable for chronotropy and inotropy; however, they maintain electrical stability during adrenergic stimulation by modulating a physiological RyR2-mediated Ca2+ leak. Zheng et al. generated a mouse model of phospho-ablation in all canonical ryanodine receptor 2 (RyR2) phosphorylation sites. They show that RyR2 phosphorylation at these sites is dispensable for chronotropy and inotropy but is required to maintain electrical stability during adrenergic stimulation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"976-990"},"PeriodicalIF":10.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144839234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-29DOI: 10.1038/s44161-025-00686-2
Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang
Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage. By regulating the level of accessible cholesterol on endothelial cells via OSBP/ORP-mediated transport, tetraspanin tunes the balance of Cdc42 and RhoA activities to affect vascular inflammation. Reducing accessible cholesterol by statin treatment or blocking its non-vesicular transport by OSBP/ORP inhibition can limit vascular inflammation.
{"title":"Tetraspanin-enriched membrane domains regulate vascular leakage by altering membrane cholesterol accessibility to balance antagonistic GTPases","authors":"Yingjun Ding, Junxiong Chen, Songlan Liu, Jennifer M. Hays, Xiaowu Gu, Jonathan D. Wren, Constantin Georgescu, Darlene N. Reuter, Beibei Liu, Furong He, Xuejun Wang, Quan Wei, Jie Wang, Bharathiraja Subramaniyan, Zhiping Wu, Kiran Kodali, Alaina M. Reagan, Willard M. Freeman, Cindy K. Miranti, Anna Csiszar, Zoltan Ungvari, Kamiya Mehla, Matthew S. Walters, Michael H. Elliott, Junmin Peng, Tomoharu Kanie, James F. Papin, Franklin A. Hays, Xin A. Zhang","doi":"10.1038/s44161-025-00686-2","DOIUrl":"10.1038/s44161-025-00686-2","url":null,"abstract":"Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage. By regulating the level of accessible cholesterol on endothelial cells via OSBP/ORP-mediated transport, tetraspanin tunes the balance of Cdc42 and RhoA activities to affect vascular inflammation. Reducing accessible cholesterol by statin treatment or blocking its non-vesicular transport by OSBP/ORP inhibition can limit vascular inflammation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 8","pages":"1011-1033"},"PeriodicalIF":10.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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