Pub Date : 2025-10-22DOI: 10.1161/circresaha.125.326235
Yunhye Kim,Giovanni Maroli,Chen-Shan Chen Woodcock,Hyunbum Kim,Yu Liu,Tim Klouda,Yan Li,Qin Li,Yuan Hao,Valerie Schumacher,Helena A Turton,A A Roger Thompson,Mario Looso,Carsten Kuenne,Chanil Valasarajan,Clemens Ruppert,Theodore Avolio,Ying Tang,Yi-Yin Tai,Tatiana V Kudryashova,Elena A Goncharova,Joseph C Wu,Jin Billy Li,Thomas Bertero,Rajkumar Savai,Benjamin A Raby,Stephen Y Chan,Soni S Pullamsetti,Ke Yuan
BACKGROUNDADAR1 (adenosine deaminase acting on RNA 1) catalyzes the conversion of adenosine to inosine in double-stranded RNAs, which is critical to prevent autoinflammatory responses mediated by activation of the type I IFN (interferon) signaling. We define the role of ADAR1-dependent RNA editing in IFNβ activation and pulmonary artery smooth muscle cell remodeling in pulmonary arterial hypertension, a devastating disease leading to right heart failure and death.METHODSRNA editing levels were analyzed in pulmonary arterial smooth muscle cells from idiopathic pulmonary arterial hypertension patients versus healthy controls. A conditional transgenic model, Adar1SMC-KO, was generated by knocking out Adar1 selectively in α-SMA (smooth muscle actin)-expressing cells, followed by 3 weeks of hypoxic exposure to induce PH.RESULTSPulmonary arterial smooth muscle cells from patients with idiopathic pulmonary arterial hypertension displayed decreased levels of ADAR1 mRNA and isoform p150 protein, accompanied by accumulated double-stranded RNA compared with healthy pulmonary arterial smooth muscle cells. ADAR1 knockdown in pulmonary arterial smooth muscle cells upregulated MDA5 (melanoma differentiation-associated protein 5), PKR (protein kinase R), IFNβ, and IFN-stimulated genes. Compared with controls in vivo, hypoxic Adar1SMC-KO mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles and increased endothelium leakage, resulting in elevated right ventricular systolic pressure and right ventricular hypertrophy. Mechanistically, Ifnβ signaling in Adar1SMC-KO induced the recruitment of macrophages, enhancing pulmonary artery muscularization. Pharmacological treatment with PKR-relevant inhibitor 2BAct decreased Ifnβ and macrophages, thus attenuating PH in hypoxic Adar1SMC-KO mice.CONCLUSIONSOur study describes a fundamental molecular mechanism underlying the progression of PH. We highlight the detrimental role of innate immune responses, where smooth muscle cell and context-specific RNA editing, along with the sensing of double-stranded RNA, mediate disease progression and excessive vascular remodeling. This finding suggests that targeting PKR could be the new therapeutic strategy for treating pulmonary arterial hypertension.
{"title":"Deficiency of Smooth Muscle ADAR1 Exacerbates Vascular Remodeling and Pulmonary Hypertension.","authors":"Yunhye Kim,Giovanni Maroli,Chen-Shan Chen Woodcock,Hyunbum Kim,Yu Liu,Tim Klouda,Yan Li,Qin Li,Yuan Hao,Valerie Schumacher,Helena A Turton,A A Roger Thompson,Mario Looso,Carsten Kuenne,Chanil Valasarajan,Clemens Ruppert,Theodore Avolio,Ying Tang,Yi-Yin Tai,Tatiana V Kudryashova,Elena A Goncharova,Joseph C Wu,Jin Billy Li,Thomas Bertero,Rajkumar Savai,Benjamin A Raby,Stephen Y Chan,Soni S Pullamsetti,Ke Yuan","doi":"10.1161/circresaha.125.326235","DOIUrl":"https://doi.org/10.1161/circresaha.125.326235","url":null,"abstract":"BACKGROUNDADAR1 (adenosine deaminase acting on RNA 1) catalyzes the conversion of adenosine to inosine in double-stranded RNAs, which is critical to prevent autoinflammatory responses mediated by activation of the type I IFN (interferon) signaling. We define the role of ADAR1-dependent RNA editing in IFNβ activation and pulmonary artery smooth muscle cell remodeling in pulmonary arterial hypertension, a devastating disease leading to right heart failure and death.METHODSRNA editing levels were analyzed in pulmonary arterial smooth muscle cells from idiopathic pulmonary arterial hypertension patients versus healthy controls. A conditional transgenic model, Adar1SMC-KO, was generated by knocking out Adar1 selectively in α-SMA (smooth muscle actin)-expressing cells, followed by 3 weeks of hypoxic exposure to induce PH.RESULTSPulmonary arterial smooth muscle cells from patients with idiopathic pulmonary arterial hypertension displayed decreased levels of ADAR1 mRNA and isoform p150 protein, accompanied by accumulated double-stranded RNA compared with healthy pulmonary arterial smooth muscle cells. ADAR1 knockdown in pulmonary arterial smooth muscle cells upregulated MDA5 (melanoma differentiation-associated protein 5), PKR (protein kinase R), IFNβ, and IFN-stimulated genes. Compared with controls in vivo, hypoxic Adar1SMC-KO mice developed severe PH, as evidenced by excessive vascular remodeling in distal arterioles and increased endothelium leakage, resulting in elevated right ventricular systolic pressure and right ventricular hypertrophy. Mechanistically, Ifnβ signaling in Adar1SMC-KO induced the recruitment of macrophages, enhancing pulmonary artery muscularization. Pharmacological treatment with PKR-relevant inhibitor 2BAct decreased Ifnβ and macrophages, thus attenuating PH in hypoxic Adar1SMC-KO mice.CONCLUSIONSOur study describes a fundamental molecular mechanism underlying the progression of PH. We highlight the detrimental role of innate immune responses, where smooth muscle cell and context-specific RNA editing, along with the sensing of double-stranded RNA, mediate disease progression and excessive vascular remodeling. This finding suggests that targeting PKR could be the new therapeutic strategy for treating pulmonary arterial hypertension.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"39 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338671","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}
Pub Date : 2025-10-15DOI: 10.1161/circresaha.125.327060
David Rodriguez Morales,Veronica Larcher,Mariano Ruz Jurado,Denada Arifaj,Lukas Tombor,Lukas Zanders,Andreas M Zeiher,Christoph Kuppe,David John,Julian U G Wagner,Marcel H Schulz,Stefanie Dimmeler
BACKGROUNDAging is a major, yet unmodifiable, cardiovascular risk factor and is associated with vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations within the multicellular architecture of the cardiac tissue is unknown.METHODSWe investigated local microenvironments in aged mice hearts by applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics of 3- and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. We treated mice with broad-spectrum senolytics dasatinib and quercetin, and endothelial-specific senolytic fisetin and studied their effects on senescence and macrophage populations.RESULTSIntegration of spatial transcriptomics data across 3- and 18-month-old hearts allowed the identification of 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but led to distinct regional changes, particularly in the left ventricle. While cardiomyocyte-enriched niches showed disrupted circadian clock gene expression, vascular niches showed major changes in proinflammatory and profibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and bone marrow-derived Lyve1- and resident Lyve1+ macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescent cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. Removal of senescent cells by senolytics reduced the presence of Lyve1- macrophages.CONCLUSIONSOur findings indicate that the perivascular microenvironment is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so-called inflammaging. This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.
{"title":"Vascular Niches Are the Primary Hotspots in Cardiac Aging.","authors":"David Rodriguez Morales,Veronica Larcher,Mariano Ruz Jurado,Denada Arifaj,Lukas Tombor,Lukas Zanders,Andreas M Zeiher,Christoph Kuppe,David John,Julian U G Wagner,Marcel H Schulz,Stefanie Dimmeler","doi":"10.1161/circresaha.125.327060","DOIUrl":"https://doi.org/10.1161/circresaha.125.327060","url":null,"abstract":"BACKGROUNDAging is a major, yet unmodifiable, cardiovascular risk factor and is associated with vascular alterations, increased cardiac fibrosis, and inflammation, all of which contribute to impaired cardiac function. However, the microenvironment inciting age-related alterations within the multicellular architecture of the cardiac tissue is unknown.METHODSWe investigated local microenvironments in aged mice hearts by applying an integrative approach combining single-nucleus RNA sequencing and spatial transcriptomics of 3- and 18-month-old mice. We defined distinct cardiac niches and studied changes in their cellular composition and functional characteristics. We treated mice with broad-spectrum senolytics dasatinib and quercetin, and endothelial-specific senolytic fisetin and studied their effects on senescence and macrophage populations.RESULTSIntegration of spatial transcriptomics data across 3- and 18-month-old hearts allowed the identification of 11 cardiac niches, which were characterized by distinct cellular composition and functional signatures. Aging did not alter the overall proportions of cardiac niches but led to distinct regional changes, particularly in the left ventricle. While cardiomyocyte-enriched niches showed disrupted circadian clock gene expression, vascular niches showed major changes in proinflammatory and profibrotic signatures and altered cellular composition. We particularly identified larger vessel-associated cellular niches as key hotspots for activated fibroblasts and bone marrow-derived Lyve1- and resident Lyve1+ macrophages in aged hearts, with interactions of both cell types through the C3:C3ar1 axis. These niches were also enriched in senescent cells exhibiting high expression of immune evasion mechanisms that may impair senescent cell clearance. Removal of senescent cells by senolytics reduced the presence of Lyve1- macrophages.CONCLUSIONSOur findings indicate that the perivascular microenvironment is particularly susceptible to age-related changes and serves as a primary site for inflammation-driven aging, so-called inflammaging. This study provides new insights into how aging reshapes cardiac cellular architecture, highlighting vessel-associated niches as potential therapeutic targets for age-related cardiac dysfunction.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"42 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288426","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}
Pub Date : 2025-10-15DOI: 10.1161/circresaha.124.325658
Julius Ryan D Pronto,Fleur E Mason,Eva A Rog-Zielinska,Funsho E Fakuade,Donata Bülow,Marcell Tóth,Khaled Machwart,Paulina Brandes,Felix Wiedmann,Michael Kohlhaas,Alexander Nickel,Matthias Wolf,Julian Mustroph,Kim-Chi Vu,Sören Brandenburg,Tri Q Do,Peter Joshua Siedler,Katharina Ritzenhoff,Zongqian Xue,Xiaobo Zhou,Stefanie Kestel,Olga Dschun,Oksana Kyshynska,George Kensah,Robyn T Rebbeck,Aschraf El-Essawi,Ahmad Fawad Jebran,Bernhard C Danner,Hassina Baraki,Johann Schredelseker,Ivan Bogeski,Bianca J J M Brundel,Stephan E Lehnart,Constanze Bening,Ingo Kutschka,Felix Bremmer,Stefan Kallenberger,Silvio O Rizzoli,Björn C Knollmann,Stefan Neef,Katrin Streckfuss-Bömeke,Constanze Schmidt,Christoph Maack,Niels Voigt
BACKGROUNDMitochondrial calcium (Ca2+) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca2+ transient amplitude, but its effect on mitochondrial Ca2+ handling and cellular redox state has not been explored in AF.METHODSCardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, NAD(P)H/flavin adenine dinucleotide autofluorescence, cytosolic and mitochondrial [Ca2+] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.RESULTSMitochondrial Ca2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell-derived myocytes, where nocodazole treatment displaces mitochondria and increases proarrhythmic Ca2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment.CONCLUSIONSMitochondrial Ca2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca2+ transfer in AF. Enhancing mitochondrial Ca2+ uptake potentially protects against arrhythmogenic events.
{"title":"Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation.","authors":"Julius Ryan D Pronto,Fleur E Mason,Eva A Rog-Zielinska,Funsho E Fakuade,Donata Bülow,Marcell Tóth,Khaled Machwart,Paulina Brandes,Felix Wiedmann,Michael Kohlhaas,Alexander Nickel,Matthias Wolf,Julian Mustroph,Kim-Chi Vu,Sören Brandenburg,Tri Q Do,Peter Joshua Siedler,Katharina Ritzenhoff,Zongqian Xue,Xiaobo Zhou,Stefanie Kestel,Olga Dschun,Oksana Kyshynska,George Kensah,Robyn T Rebbeck,Aschraf El-Essawi,Ahmad Fawad Jebran,Bernhard C Danner,Hassina Baraki,Johann Schredelseker,Ivan Bogeski,Bianca J J M Brundel,Stephan E Lehnart,Constanze Bening,Ingo Kutschka,Felix Bremmer,Stefan Kallenberger,Silvio O Rizzoli,Björn C Knollmann,Stefan Neef,Katrin Streckfuss-Bömeke,Constanze Schmidt,Christoph Maack,Niels Voigt","doi":"10.1161/circresaha.124.325658","DOIUrl":"https://doi.org/10.1161/circresaha.124.325658","url":null,"abstract":"BACKGROUNDMitochondrial calcium (Ca2+) is a key regulator of cardiac energetics by stimulating the tricarboxylic acid cycle during elevated workload. Atrial fibrillation (AF) is associated with a reduction in cytosolic Ca2+ transient amplitude, but its effect on mitochondrial Ca2+ handling and cellular redox state has not been explored in AF.METHODSCardiac myocytes isolated from patient-derived right atrial biopsies were subjected to workload transitions using patch-clamp stimulation and β-adrenergic stimulation (isoproterenol). In conjunction, NAD(P)H/flavin adenine dinucleotide autofluorescence, cytosolic and mitochondrial [Ca2+] were monitored using epifluorescence microscopy. Sarcoplasmic reticulum and mitochondria were imaged using electron tomography and stimulated emission depletion microscopy. The effects of the mitochondrial Ca2+ uptake enhancer ezetimibe on proarrhythmic activity in atrial myocytes and on AF burden in patients were investigated.RESULTSMitochondrial Ca2+ accumulation during increased workload was blunted in AF, and was associated with impaired regeneration of nicotinamide adenine dinucleotide and flavin adenine dinucleotide. Nanoscale imaging revealed spatial disorganization of sarcoplasmic reticulum and mitochondria, associated with microtubule destabilization. This was confirmed in human induced pluripotent stem cell-derived myocytes, where nocodazole treatment displaces mitochondria and increases proarrhythmic Ca2+ sparks, which were rescued by MitoTEMPO. Ezetimibe also reduced the occurrence of arrhythmogenic Ca2+ release events both in AF myocytes and nocodazole-treated human induced pluripotent stem cell-derived cardiac myocytes. Retrospective patient analysis also revealed a reduced AF burden in patients on ezetimibe treatment.CONCLUSIONSMitochondrial Ca2+ uptake and accumulation are impaired in atrial myocytes from patients with AF. The disturbed spatial association between sarcoplasmic reticulum and mitochondria driven by destabilized microtubules may underlie impaired Ca2+ transfer in AF. Enhancing mitochondrial Ca2+ uptake potentially protects against arrhythmogenic events.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288383","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}
Pub Date : 2025-10-15DOI: 10.1161/circresaha.125.327050
Blandine Chazarin,Aleksandra Binek,Johannes Janssens,Lindsey Becker,Simion Kreimer,Ali Haghani,Joshua Cantlon,Janet Pham,Alexandre Hutton,Jesse G Meyer,Jonathan R Krieger,Yanis Zirem,Anja Karlstaedt,Jennifer E Van Eyk
{"title":"SCarP: Proteome Heterogeneity Characterization of Primary Mouse Cardiomyocytes.","authors":"Blandine Chazarin,Aleksandra Binek,Johannes Janssens,Lindsey Becker,Simion Kreimer,Ali Haghani,Joshua Cantlon,Janet Pham,Alexandre Hutton,Jesse G Meyer,Jonathan R Krieger,Yanis Zirem,Anja Karlstaedt,Jennifer E Van Eyk","doi":"10.1161/circresaha.125.327050","DOIUrl":"https://doi.org/10.1161/circresaha.125.327050","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288382","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}
Pub Date : 2025-10-10Epub Date: 2025-10-09DOI: 10.1161/RES.0000000000000734
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000734","DOIUrl":"https://doi.org/10.1161/RES.0000000000000734","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 9","pages":"1137-1139"},"PeriodicalIF":16.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257554","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}
BACKGROUNDThe homeostatic chemokine CCL21 (C-C motif chemokine ligand 21) is abnormally elevated in coronary artery disease. Plasma CCL21 levels have been found to be independently associated with adverse outcomes after acute coronary syndrome. However, the specific effects of CCL21 on coronary artery disease-associated platelet activation and thrombosis remain poorly understood.METHODSWe examined the effects of CCL21 on platelet activation, spreading, clot retraction, in vitro shear stress-induced thrombus formation, in vivo arterial thrombus formation, middle cerebral artery occlusion-induced brain injury, and myocardial ischemia-reperfusion injury. We also investigated the underlying mechanisms and the therapeutic impacts of a CCL21 antibody on platelet activation and in vivo thrombosis in atherosclerosis.RESULTSCCL21 potentiated agonist-induced platelet activation, including aggregation, dense granule release, P-selectin exposure, integrin αIIbβ3 activation, spreading, and clot retraction. Furthermore, CCL21 enhanced in vivo thrombosis, whole blood thrombus formation, and middle cerebral artery occlusion-induced brain injury. Mechanistically, CCL21 binds to platelet CCR7 (C-C motif chemokine receptor 7), a G-protein-coupled receptor previously unreported in platelets, activating Gi and G13 signaling pathways to enhance platelet activation. A CCL21 antibody attenuated platelet activation and inhibited in vivo thrombosis in patients with coronary artery disease and atherosclerotic ApoE-/- mice. In addition, this antibody mitigated microvascular thrombosis, safeguarding the hearts of atherosclerotic ApoE-/- mice from severe ischemia-reperfusion injury.CONCLUSIONSCCL21 enhances platelet activation and atherothrombosis by binding to platelet CCR7 and thus activating downstream Gi and G13 signaling pathways. A CCL21 antibody can counteract these effects in the context of coronary artery disease, supporting its potential as a preventive therapy for thrombotic complications.
{"title":"CCL21 Enhances Platelet Activation and Atherothrombosis via CCR7 Activation.","authors":"Xin Liu,Peng Zhang,Zhexun Lia,Haichu Yu,Yonghong Li,Junjie Guo,Ning Zhang,Shimo Dai,Zhiyong Qi,Junbo Ge","doi":"10.1161/circresaha.125.326784","DOIUrl":"https://doi.org/10.1161/circresaha.125.326784","url":null,"abstract":"BACKGROUNDThe homeostatic chemokine CCL21 (C-C motif chemokine ligand 21) is abnormally elevated in coronary artery disease. Plasma CCL21 levels have been found to be independently associated with adverse outcomes after acute coronary syndrome. However, the specific effects of CCL21 on coronary artery disease-associated platelet activation and thrombosis remain poorly understood.METHODSWe examined the effects of CCL21 on platelet activation, spreading, clot retraction, in vitro shear stress-induced thrombus formation, in vivo arterial thrombus formation, middle cerebral artery occlusion-induced brain injury, and myocardial ischemia-reperfusion injury. We also investigated the underlying mechanisms and the therapeutic impacts of a CCL21 antibody on platelet activation and in vivo thrombosis in atherosclerosis.RESULTSCCL21 potentiated agonist-induced platelet activation, including aggregation, dense granule release, P-selectin exposure, integrin αIIbβ3 activation, spreading, and clot retraction. Furthermore, CCL21 enhanced in vivo thrombosis, whole blood thrombus formation, and middle cerebral artery occlusion-induced brain injury. Mechanistically, CCL21 binds to platelet CCR7 (C-C motif chemokine receptor 7), a G-protein-coupled receptor previously unreported in platelets, activating Gi and G13 signaling pathways to enhance platelet activation. A CCL21 antibody attenuated platelet activation and inhibited in vivo thrombosis in patients with coronary artery disease and atherosclerotic ApoE-/- mice. In addition, this antibody mitigated microvascular thrombosis, safeguarding the hearts of atherosclerotic ApoE-/- mice from severe ischemia-reperfusion injury.CONCLUSIONSCCL21 enhances platelet activation and atherothrombosis by binding to platelet CCR7 and thus activating downstream Gi and G13 signaling pathways. A CCL21 antibody can counteract these effects in the context of coronary artery disease, supporting its potential as a preventive therapy for thrombotic complications.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"126 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254487","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}
Pub Date : 2025-10-09DOI: 10.1161/circresaha.125.327130
Zhe Yu,Thomas Moore-Morris,Sylvia M Evans
{"title":"Unraveling the Link Between Cardiomyocyte Endoreplication and Hypertrophy.","authors":"Zhe Yu,Thomas Moore-Morris,Sylvia M Evans","doi":"10.1161/circresaha.125.327130","DOIUrl":"https://doi.org/10.1161/circresaha.125.327130","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"26 1","pages":"1182-1184"},"PeriodicalIF":20.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254490","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}
Pub Date : 2025-10-07DOI: 10.1161/circresaha.125.326221
Shanmugasundaram Pakkiriswami,Jae Hwi Sung,Kshama R Shah,Ulas Ozkurede,Megan K Sumera,Feng Feng,Hector Chapoy Villanueva,Eun Suh Cho,Andrea Torniainen,Jop van Berlo,Gyorgy Hajnoczky,Kurt W Prins,Julia C Liu
BACKGROUNDMitochondrial ATP production, essential for cardiomyocyte function, is regulated by mitochondrial Ca2+ (mtCa2+). The primary route for mtCa2+ influx is the mitochondrial calcium uniporter complex. The mitochondrial calcium uniporter complex subunit MICU (mitochondrial calcium uptake) 1 limits mtCa2+ uptake, preventing mtCa2+ overload. Although elevated mtCa2+ has been observed in multiple diseases including heart failure, its effects on heart function remain elusive.METHODSTo investigate the impact of elevated mtCa2+ in adult hearts, we generated a mouse model with cardiomyocyte-specific tamoxifen-inducible Micu1 deletion (Micu1cKO). Cardiac function was assessed through echocardiography. Mitochondria, adult cardiomyocytes, and tissue extracts were isolated from the left ventricle (LV) and right ventricle (RV) for comprehensive analysis at multiple time points ranging from 1 to 9 weeks post-tamoxifen injection.RESULTSAcute MICU1 deficiency resulted in increased mtCa2+ accompanied by reduced mitochondrial respiration in both the RV and LV. Contractile function, which was diminished in both ventricles initially, remained reduced in the RV upon prolonged MICU1 deficiency. In contrast, the LV exhibited signs of recovery over time, including restored ejection fraction concurrent with normalization of mtCa2+ levels. This pattern was mirrored in cardiomyocyte contractility. In Micu1cKO RV, mtCa2+ remained elevated, likely contributing to oxidative stress. As a potential mechanism underlying LV-specific recovery, EMRE (essential MCU regulator), an mitochondrial calcium uniporter complex subunit that promotes mtCa2+ uptake, was found to be downregulated only in the LV. This suggested that the LV initiated a compensatory response to elevated mtCa2+, while the RV remained impacted. Supporting this, proteomics analysis indicated a divergent proteomic signature in Micu1cKO RV. Follow-up experiments suggested enhanced EMRE degradation in Micu1cKO LV mediated by m-AAA proteases through a PKA (protein kinase A)-regulated mechanism. In MICU1-deficient neonatal cardiomyocytes, pharmacological PKA inhibition was sufficient to decrease EMRE levels. Analysis of LV tissues from patients with dilated cardiomyopathy suggested that this pathway may be relevant in human DCM.CONCLUSIONSWhile elevated mtCa2+ disrupted cardiac function in both ventricles, it induced an LV-specific adaptive response that suppressed mtCa2+ intake, contributing to the recovery of mitochondrial and cardiac function. The absence of this pathway in the RV has implications for therapeutics targeting RV dysfunction, a key determinant of mortality in heart failure.
{"title":"Adaptation to Elevated Mitochondrial Calcium Is Distinct in the Left and Right Ventricles.","authors":"Shanmugasundaram Pakkiriswami,Jae Hwi Sung,Kshama R Shah,Ulas Ozkurede,Megan K Sumera,Feng Feng,Hector Chapoy Villanueva,Eun Suh Cho,Andrea Torniainen,Jop van Berlo,Gyorgy Hajnoczky,Kurt W Prins,Julia C Liu","doi":"10.1161/circresaha.125.326221","DOIUrl":"https://doi.org/10.1161/circresaha.125.326221","url":null,"abstract":"BACKGROUNDMitochondrial ATP production, essential for cardiomyocyte function, is regulated by mitochondrial Ca2+ (mtCa2+). The primary route for mtCa2+ influx is the mitochondrial calcium uniporter complex. The mitochondrial calcium uniporter complex subunit MICU (mitochondrial calcium uptake) 1 limits mtCa2+ uptake, preventing mtCa2+ overload. Although elevated mtCa2+ has been observed in multiple diseases including heart failure, its effects on heart function remain elusive.METHODSTo investigate the impact of elevated mtCa2+ in adult hearts, we generated a mouse model with cardiomyocyte-specific tamoxifen-inducible Micu1 deletion (Micu1cKO). Cardiac function was assessed through echocardiography. Mitochondria, adult cardiomyocytes, and tissue extracts were isolated from the left ventricle (LV) and right ventricle (RV) for comprehensive analysis at multiple time points ranging from 1 to 9 weeks post-tamoxifen injection.RESULTSAcute MICU1 deficiency resulted in increased mtCa2+ accompanied by reduced mitochondrial respiration in both the RV and LV. Contractile function, which was diminished in both ventricles initially, remained reduced in the RV upon prolonged MICU1 deficiency. In contrast, the LV exhibited signs of recovery over time, including restored ejection fraction concurrent with normalization of mtCa2+ levels. This pattern was mirrored in cardiomyocyte contractility. In Micu1cKO RV, mtCa2+ remained elevated, likely contributing to oxidative stress. As a potential mechanism underlying LV-specific recovery, EMRE (essential MCU regulator), an mitochondrial calcium uniporter complex subunit that promotes mtCa2+ uptake, was found to be downregulated only in the LV. This suggested that the LV initiated a compensatory response to elevated mtCa2+, while the RV remained impacted. Supporting this, proteomics analysis indicated a divergent proteomic signature in Micu1cKO RV. Follow-up experiments suggested enhanced EMRE degradation in Micu1cKO LV mediated by m-AAA proteases through a PKA (protein kinase A)-regulated mechanism. In MICU1-deficient neonatal cardiomyocytes, pharmacological PKA inhibition was sufficient to decrease EMRE levels. Analysis of LV tissues from patients with dilated cardiomyopathy suggested that this pathway may be relevant in human DCM.CONCLUSIONSWhile elevated mtCa2+ disrupted cardiac function in both ventricles, it induced an LV-specific adaptive response that suppressed mtCa2+ intake, contributing to the recovery of mitochondrial and cardiac function. The absence of this pathway in the RV has implications for therapeutics targeting RV dysfunction, a key determinant of mortality in heart failure.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"30 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235755","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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