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}
Pub Date : 2025-10-01DOI: 10.1161/circresaha.125.326522
Soah Lee,Paul Heinrich,Daniel Lee,Yongwon Kang,Harley Robinson,Sean J Humphrey,Jihye Yun,William R Goodyer,Jan W Buikema,David T Paik,Francisco X Galdos,Boyoung Kim,Nadjet Belbachir,Sungjin Min,Seung-Woo Cho,Jaecheol Lee,Alessandra Moretti,Joseph C Wu,James Hudson,Sean M Wu
BACKGROUNDInduction of cardiomyocyte proliferation in situ represents a promising strategy for myocardial regeneration following injury. However, cardiomyocytes possess intrinsic inhibitory mechanisms that attenuate pro-proliferative signaling and constrain their expansion. We hypothesized that cell-cell contact is a key suppressor of cardiomyocyte proliferation. We aimed to delineate the underlying molecular pathways to enable sustained proliferation in 3-dimensional contexts.METHODSHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured at varying plating densities to examine the impact of cell-cell contact on cell cycle activity. Phosphoproteomic profiling was performed in sparse versus dense cultures to identify signaling alterations. Conditioned media from sparse cultures were interrogated using a human growth factor array to identify secreted pro-proliferative factors.RESULTShiPSC-CM proliferation increased proportionally with plating density until intercellular contacts were established, at which point proliferation was suppressed. Dense cultures exhibited enhanced adherens junction assembly, sarcomeric organization, and contractile function. Increased cell-cell contact in dense conditions attenuated nuclear translocation of β-catenin and reduced TCF/LEF transcriptional activity, providing a mechanistic basis for the reduced hiPSC-CM proliferation. Disruption of adherens junctions or sarcomere assembly via siRNA-mediated knockdown of N-cadherin or α-actinin, respectively, resulted in increased cell cycle activation of hiPSC-CMs, but this was not sufficient to drive division of hiPSC-CMs. Additional screening for putative secreted growth factors in the conditioned media from sparsely plated hiPSC-CMs revealed the enrichment of IGFBP2, which was sufficient to drive hiPSC-CM division in the presence of cell-cell contact in 3-dimensional constructs.CONCLUSIONSOur findings demonstrate that cell-cell contact inhibits hiPSC-CM proliferation through adherens junction formation, sarcomeric assembly, and reduced IGFBP2 secretion. Importantly, exogenous supplementation of IGFBP2 can overcome cell contact-mediated inhibition of hiPSC-CM proliferation and facilitate the growth of 3-dimensional cardiac tissue. These insights provide valuable implications for advancing cardiac tissue engineering and regenerative therapies.
{"title":"IGFBP2 Mediates Human iPSC-Cardiomyocyte Proliferation in a Cellular Contact-Dependent Manner.","authors":"Soah Lee,Paul Heinrich,Daniel Lee,Yongwon Kang,Harley Robinson,Sean J Humphrey,Jihye Yun,William R Goodyer,Jan W Buikema,David T Paik,Francisco X Galdos,Boyoung Kim,Nadjet Belbachir,Sungjin Min,Seung-Woo Cho,Jaecheol Lee,Alessandra Moretti,Joseph C Wu,James Hudson,Sean M Wu","doi":"10.1161/circresaha.125.326522","DOIUrl":"https://doi.org/10.1161/circresaha.125.326522","url":null,"abstract":"BACKGROUNDInduction of cardiomyocyte proliferation in situ represents a promising strategy for myocardial regeneration following injury. However, cardiomyocytes possess intrinsic inhibitory mechanisms that attenuate pro-proliferative signaling and constrain their expansion. We hypothesized that cell-cell contact is a key suppressor of cardiomyocyte proliferation. We aimed to delineate the underlying molecular pathways to enable sustained proliferation in 3-dimensional contexts.METHODSHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured at varying plating densities to examine the impact of cell-cell contact on cell cycle activity. Phosphoproteomic profiling was performed in sparse versus dense cultures to identify signaling alterations. Conditioned media from sparse cultures were interrogated using a human growth factor array to identify secreted pro-proliferative factors.RESULTShiPSC-CM proliferation increased proportionally with plating density until intercellular contacts were established, at which point proliferation was suppressed. Dense cultures exhibited enhanced adherens junction assembly, sarcomeric organization, and contractile function. Increased cell-cell contact in dense conditions attenuated nuclear translocation of β-catenin and reduced TCF/LEF transcriptional activity, providing a mechanistic basis for the reduced hiPSC-CM proliferation. Disruption of adherens junctions or sarcomere assembly via siRNA-mediated knockdown of N-cadherin or α-actinin, respectively, resulted in increased cell cycle activation of hiPSC-CMs, but this was not sufficient to drive division of hiPSC-CMs. Additional screening for putative secreted growth factors in the conditioned media from sparsely plated hiPSC-CMs revealed the enrichment of IGFBP2, which was sufficient to drive hiPSC-CM division in the presence of cell-cell contact in 3-dimensional constructs.CONCLUSIONSOur findings demonstrate that cell-cell contact inhibits hiPSC-CM proliferation through adherens junction formation, sarcomeric assembly, and reduced IGFBP2 secretion. Importantly, exogenous supplementation of IGFBP2 can overcome cell contact-mediated inhibition of hiPSC-CM proliferation and facilitate the growth of 3-dimensional cardiac tissue. These insights provide valuable implications for advancing cardiac tissue engineering and regenerative therapies.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"93 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194828","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}
BACKGROUNDNeutrophil extracellular traps (NETs) contribute to atherosclerosis progression and are linked to adverse clinical outcomes such as myocardial infarction and stroke. Although the triggers of NET formation in plaques are known, the mechanisms governing DNase-mediated NET clearance and how these are disrupted during atherosclerosis remain unclear. Moreover, the consequences of impaired NET clearance on disease progression are not known.METHODSLow-density lipoprotein receptor knockout (Ldlr-/-) mice with hematopoietic cell-specific deletion of DNase1 and DNase1L3 were fed a Western-type diet for 16 weeks to examine the impact of loss of DNase activity and the subsequent NET accumulation on advanced atherosclerosis. The effect of NETs on macrophage efferocytosis was examined in vitro and in the mouse peritoneal cavity and atherosclerotic plaque in vivo. To identify the signaling pathway impairing the NET-induced DNase response, in vitro assays were performed using selective endoplasmic reticulum stress pathway inhibitors, and the findings were validated in murine and human atherosclerotic tissues.RESULTSLack of DNase secretion by macrophages led to accumulation of NETs in local tissues, including atherosclerotic plaques. Persisting NETs in turn promoted cleavage of the efferocytosis receptor MerTK, resulting in defective macrophage efferocytosis and increased atherosclerotic plaque necrosis. In vitro screening identified endoplasmic reticulum stress-induced activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-ATF (activating transcription factor) 4 signaling axis in atherogenic macrophages as a key driver of impaired DNase secretion, leading to delayed NET clearance and their pathological persistence. Treatment of human atherosclerotic plaques and Ldlr-/- mice with integrated stress response inhibitor, a selective PERK inhibitor, restored vascular DNase secretion and facilitated NET clearance.CONCLUSIONSMacrophages play a key role in clearing NETs from tissues. Endoplasmic reticulum stress suppresses macrophage DNase secretion, leading to NET accumulation in atherosclerotic plaques, which triggers efferocytosis impairment and plaque progression. Targeting the PERK-ATF4 axis to restore DNase release and NET clearance represents a promising therapeutic strategy to promote plaque stabilization.
{"title":"Macrophage DNases Limit Neutrophil Extracellular Trap-Mediated Defective Efferocytosis in Atherosclerosis.","authors":"Umesh Kumar Dhawan,Tanwi Vartak,Hanna Englert,Stefan Russo,Luiz Ricardo C Vasconcellos,Aarushi Singhal,Rahul Chakraborty,Karran Kiran Bhagat,Ciaran McDonnell,Mary Connolly,Edward Mulkern,Martin O'Donohoe,Mathias Gelderblom,Thomas Renne,Catherine Godson,Eoin Brennan,Manikandan Subramanian","doi":"10.1161/circresaha.125.326353","DOIUrl":"https://doi.org/10.1161/circresaha.125.326353","url":null,"abstract":"BACKGROUNDNeutrophil extracellular traps (NETs) contribute to atherosclerosis progression and are linked to adverse clinical outcomes such as myocardial infarction and stroke. Although the triggers of NET formation in plaques are known, the mechanisms governing DNase-mediated NET clearance and how these are disrupted during atherosclerosis remain unclear. Moreover, the consequences of impaired NET clearance on disease progression are not known.METHODSLow-density lipoprotein receptor knockout (Ldlr-/-) mice with hematopoietic cell-specific deletion of DNase1 and DNase1L3 were fed a Western-type diet for 16 weeks to examine the impact of loss of DNase activity and the subsequent NET accumulation on advanced atherosclerosis. The effect of NETs on macrophage efferocytosis was examined in vitro and in the mouse peritoneal cavity and atherosclerotic plaque in vivo. To identify the signaling pathway impairing the NET-induced DNase response, in vitro assays were performed using selective endoplasmic reticulum stress pathway inhibitors, and the findings were validated in murine and human atherosclerotic tissues.RESULTSLack of DNase secretion by macrophages led to accumulation of NETs in local tissues, including atherosclerotic plaques. Persisting NETs in turn promoted cleavage of the efferocytosis receptor MerTK, resulting in defective macrophage efferocytosis and increased atherosclerotic plaque necrosis. In vitro screening identified endoplasmic reticulum stress-induced activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-ATF (activating transcription factor) 4 signaling axis in atherogenic macrophages as a key driver of impaired DNase secretion, leading to delayed NET clearance and their pathological persistence. Treatment of human atherosclerotic plaques and Ldlr-/- mice with integrated stress response inhibitor, a selective PERK inhibitor, restored vascular DNase secretion and facilitated NET clearance.CONCLUSIONSMacrophages play a key role in clearing NETs from tissues. Endoplasmic reticulum stress suppresses macrophage DNase secretion, leading to NET accumulation in atherosclerotic plaques, which triggers efferocytosis impairment and plaque progression. Targeting the PERK-ATF4 axis to restore DNase release and NET clearance represents a promising therapeutic strategy to promote plaque stabilization.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"31 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194826","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 : 2025-10-01DOI: 10.1161/circresaha.125.326336
Jenna B Mendelson,Jacob D Sternbach,Minwoo Kim,Ryan A Moon,Lynn M Hartweck,Sophia R Clark,Walt Tollison,Matthew T Lahti,John P Carney,Todd Markowski,LeeAnn Higgins,Felipe Kazmirczak,Kurt W Prins
BACKGROUNDRight ventricular (RV) dysfunction is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of GP130 (glycoprotein-130) signaling with the small molecule SC144 improves RV function in rodent RV dysfunction via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy and molecular effects in a translational large animal model of RV dysfunction are unknown.METHODSFour-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144, n=5] or vehicle [PAB-Veh, n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac magnetic resonance imaging quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type-specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue and serum. Quantitative proteomics examined RV mitochondrial protein regulation. Confocal microscopy evaluated alterations in cardiomyocyte size, macrophage abundances, capillary density, and pericyte/endothelial cell localization patterns.RESULTSSC144 significantly improved RV ejection fraction (control: 60±4%; PAB-Veh: 22±10%; PAB-SC144: 37±6%) without altering RV afterload. Single-nucleus RNA sequencing demonstrated that PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared with control, and many of these changes were blunted by SC144. Immunohistochemistry validated the reduction in RV macrophage infiltration by SC144. Both transcriptomics and proteomics approaches demonstrated that SC144 combatted the downregulation of cardiomyocyte metabolic genes/proteins induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 (mammalian target of rapamycin complex 1) activation. Correspondingly, SC144 rebalanced the RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed that SC144 restored fatty acid metabolism. Finally, CellChat analysis, cardiomyocyte RNAseq analysis, and histological examination suggested SC144 rebalanced pericyte-endothelial cell interactions and blunted cardiomyocyte HIF1 (hypoxia-induced factor 1) activation.CONCLUSIONSGP130 antagonism blunts RV immune cell infiltration, reduces proinflammatory gene programs in macrophages and lymphocytes, rebalances autophagy, and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte homeostasis to mitigate cardiomyocyte hypoxia and ultimately augments RV function.
{"title":"GP130 Antagonism Enhances Porcine RV Function.","authors":"Jenna B Mendelson,Jacob D Sternbach,Minwoo Kim,Ryan A Moon,Lynn M Hartweck,Sophia R Clark,Walt Tollison,Matthew T Lahti,John P Carney,Todd Markowski,LeeAnn Higgins,Felipe Kazmirczak,Kurt W Prins","doi":"10.1161/circresaha.125.326336","DOIUrl":"https://doi.org/10.1161/circresaha.125.326336","url":null,"abstract":"BACKGROUNDRight ventricular (RV) dysfunction is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of GP130 (glycoprotein-130) signaling with the small molecule SC144 improves RV function in rodent RV dysfunction via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy and molecular effects in a translational large animal model of RV dysfunction are unknown.METHODSFour-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144, n=5] or vehicle [PAB-Veh, n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac magnetic resonance imaging quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type-specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue and serum. Quantitative proteomics examined RV mitochondrial protein regulation. Confocal microscopy evaluated alterations in cardiomyocyte size, macrophage abundances, capillary density, and pericyte/endothelial cell localization patterns.RESULTSSC144 significantly improved RV ejection fraction (control: 60±4%; PAB-Veh: 22±10%; PAB-SC144: 37±6%) without altering RV afterload. Single-nucleus RNA sequencing demonstrated that PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared with control, and many of these changes were blunted by SC144. Immunohistochemistry validated the reduction in RV macrophage infiltration by SC144. Both transcriptomics and proteomics approaches demonstrated that SC144 combatted the downregulation of cardiomyocyte metabolic genes/proteins induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 (mammalian target of rapamycin complex 1) activation. Correspondingly, SC144 rebalanced the RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed that SC144 restored fatty acid metabolism. Finally, CellChat analysis, cardiomyocyte RNAseq analysis, and histological examination suggested SC144 rebalanced pericyte-endothelial cell interactions and blunted cardiomyocyte HIF1 (hypoxia-induced factor 1) activation.CONCLUSIONSGP130 antagonism blunts RV immune cell infiltration, reduces proinflammatory gene programs in macrophages and lymphocytes, rebalances autophagy, and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte homeostasis to mitigate cardiomyocyte hypoxia and ultimately augments RV function.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194878","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 : 2025-09-30DOI: 10.1161/circresaha.125.326808
Jeremiah M Afolabi,Mohammad Saleem,Annet Kirabo,Ashley L Mutchler
{"title":"Isolevuglandins Modulate Histone H1 in Myeloid Cells in Salt-Sensitive Hypertension.","authors":"Jeremiah M Afolabi,Mohammad Saleem,Annet Kirabo,Ashley L Mutchler","doi":"10.1161/circresaha.125.326808","DOIUrl":"https://doi.org/10.1161/circresaha.125.326808","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"5 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189311","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 : 2025-09-26Epub Date: 2025-09-03DOI: 10.1161/CIRCRESAHA.125.326823
Jasmeet S Reyat, Yuqi Shen, Gowsihan Poologasundarampillai, Amirpasha Moetazedian, Julie Rayes, Abdullah O Khan
{"title":"Human Multi-Organoid Platform to Model Immune Dynamics in Cardiac Injury and Disease.","authors":"Jasmeet S Reyat, Yuqi Shen, Gowsihan Poologasundarampillai, Amirpasha Moetazedian, Julie Rayes, Abdullah O Khan","doi":"10.1161/CIRCRESAHA.125.326823","DOIUrl":"10.1161/CIRCRESAHA.125.326823","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1133-1136"},"PeriodicalIF":16.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26Epub Date: 2025-09-25DOI: 10.1161/RES.0000000000000733
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000733","DOIUrl":"https://doi.org/10.1161/RES.0000000000000733","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 8","pages":"1049-1050"},"PeriodicalIF":16.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148174","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 : 2025-09-26Epub Date: 2025-09-03DOI: 10.1161/CIRCRESAHA.125.326541
Hiroki Yamaguchi, Nick A Guagliardo, Laura A Bell, Manako Yamaguchi, Daisuke Matsuoka, Fang Xu, Jason P Smith, Mohamed Diagne, Sophie Condron, Lucas F Almeida, Silvia Medrano, Paula Q Barrett, Edward H Nieh, R Ariel Gomez, Maria Luisa S Sequeira-Lopez
<p><strong>Background: </strong>Juxtaglomerular cells are sensors that control blood pressure and fluid-electrolyte homeostasis. They are arranged as clusters at the tip of each afferent arteriole. In response to decreased blood pressure or extracellular fluid volume, juxtaglomerular cells secrete renin, initiating an enzymatic cascade that culminates in the production of Ang II (angiotensin II), a potent vasoconstrictor that restores blood pressure and fluid-electrolyte homeostasis. In turn, Ang II exerts negative feedback on renin release commensurate with increased intracellular Ca<sup>2+</sup>, preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca<sup>2+</sup> signaling dynamics and their sources remain uncharacterized.</p><p><strong>Methods: </strong>We generated mice expressing the juxtaglomerular cell-specific genetically encoded Ca<sup>2+</sup> indicator (GCaMP6f) to investigate Ca<sup>2+</sup> dynamics within juxtaglomerular cell clusters ex vivo and in vivo. For ex vivo Ca<sup>2+</sup> imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca<sup>2+</sup> and Ang II concentrations ±Ca<sup>2+</sup> channel inhibitors. For in vivo Ca<sup>2+</sup> image capture, native mouse kidneys were imaged in situ using multiphoton microscopy with and without Ang II and Ang II type-1 receptor blocker losartan administration. ELISA measurements determined acute renin secretion ex vivo and in vivo.</p><p><strong>Results: </strong>Ex vivo Ca<sup>2+</sup> imaging revealed that juxtaglomerular cell clusters exhibit robust and coordinated intracellular oscillatory signals with cell-cell propagation following Ang II stimulation. Ang II dose-dependently induced stereotypical burst patterns characterized by consecutive Ca<sup>2+</sup> spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca<sup>2+</sup> storage and release, extracellular Ca<sup>2+</sup> uptake via store-operated ORAI (Ca<sup>2+</sup>-selective plasma membrane channels involved in store-operated Ca<sup>2+</sup> entry) Ca<sup>2+</sup> channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced Ang II inhibitory effect on renin secretion. In vivo Ca<sup>2+</sup> imaging demonstrated robust intracellular and intercellular Ca<sup>2+</sup> oscillations within juxtaglomerular cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in ex vivo preparations. Ang II administration enhanced the Ca<sup>2+</sup> oscillatory signals and suppressed acute renin secretion, whereas losartan produced inverse effects in vivo.</p><p><strong>Conclusions: </strong>Ang II elicits coordinated intracellular and intercellular Ca<sup>2+</sup> oscillations within juxtaglomerular cell
{"title":"Calcium Oscillations Within Juxtaglomerular Cell Clusters Control Renin Release.","authors":"Hiroki Yamaguchi, Nick A Guagliardo, Laura A Bell, Manako Yamaguchi, Daisuke Matsuoka, Fang Xu, Jason P Smith, Mohamed Diagne, Sophie Condron, Lucas F Almeida, Silvia Medrano, Paula Q Barrett, Edward H Nieh, R Ariel Gomez, Maria Luisa S Sequeira-Lopez","doi":"10.1161/CIRCRESAHA.125.326541","DOIUrl":"10.1161/CIRCRESAHA.125.326541","url":null,"abstract":"<p><strong>Background: </strong>Juxtaglomerular cells are sensors that control blood pressure and fluid-electrolyte homeostasis. They are arranged as clusters at the tip of each afferent arteriole. In response to decreased blood pressure or extracellular fluid volume, juxtaglomerular cells secrete renin, initiating an enzymatic cascade that culminates in the production of Ang II (angiotensin II), a potent vasoconstrictor that restores blood pressure and fluid-electrolyte homeostasis. In turn, Ang II exerts negative feedback on renin release commensurate with increased intracellular Ca<sup>2+</sup>, preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca<sup>2+</sup> signaling dynamics and their sources remain uncharacterized.</p><p><strong>Methods: </strong>We generated mice expressing the juxtaglomerular cell-specific genetically encoded Ca<sup>2+</sup> indicator (GCaMP6f) to investigate Ca<sup>2+</sup> dynamics within juxtaglomerular cell clusters ex vivo and in vivo. For ex vivo Ca<sup>2+</sup> imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca<sup>2+</sup> and Ang II concentrations ±Ca<sup>2+</sup> channel inhibitors. For in vivo Ca<sup>2+</sup> image capture, native mouse kidneys were imaged in situ using multiphoton microscopy with and without Ang II and Ang II type-1 receptor blocker losartan administration. ELISA measurements determined acute renin secretion ex vivo and in vivo.</p><p><strong>Results: </strong>Ex vivo Ca<sup>2+</sup> imaging revealed that juxtaglomerular cell clusters exhibit robust and coordinated intracellular oscillatory signals with cell-cell propagation following Ang II stimulation. Ang II dose-dependently induced stereotypical burst patterns characterized by consecutive Ca<sup>2+</sup> spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca<sup>2+</sup> storage and release, extracellular Ca<sup>2+</sup> uptake via store-operated ORAI (Ca<sup>2+</sup>-selective plasma membrane channels involved in store-operated Ca<sup>2+</sup> entry) Ca<sup>2+</sup> channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced Ang II inhibitory effect on renin secretion. In vivo Ca<sup>2+</sup> imaging demonstrated robust intracellular and intercellular Ca<sup>2+</sup> oscillations within juxtaglomerular cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in ex vivo preparations. Ang II administration enhanced the Ca<sup>2+</sup> oscillatory signals and suppressed acute renin secretion, whereas losartan produced inverse effects in vivo.</p><p><strong>Conclusions: </strong>Ang II elicits coordinated intracellular and intercellular Ca<sup>2+</sup> oscillations within juxtaglomerular cell","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1051-1068"},"PeriodicalIF":16.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12526284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26Epub Date: 2025-09-25DOI: 10.1161/RES.0000000000000732
Kara R Gouwens, Ernesto Pena Calderin, Jada Okhiria, Daniel C Nguyen, Emily B Schulman-Geltzer, Yania Martinez-Ondaro, Maleesha De Silva, Helen E Collins, Yibing Nong, Sophia M Sears, Matthew A Nystoriak, Bradford G Hill
{"title":"Correction to: Cardiac Ketone Body Oxidation Enhances Exercise Performance.","authors":"Kara R Gouwens, Ernesto Pena Calderin, Jada Okhiria, Daniel C Nguyen, Emily B Schulman-Geltzer, Yania Martinez-Ondaro, Maleesha De Silva, Helen E Collins, Yibing Nong, Sophia M Sears, Matthew A Nystoriak, Bradford G Hill","doi":"10.1161/RES.0000000000000732","DOIUrl":"https://doi.org/10.1161/RES.0000000000000732","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 8","pages":"e176"},"PeriodicalIF":16.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148203","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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