Pub Date : 2024-07-18DOI: 10.1038/s44161-024-00512-1
Aly Elezaby, Amanda J. Lin, Vijith Vijayan, Suman Pokhrel, Benjamin R. Kraemer, Luiz R. G. Bechara, Isabel Larus, Junhui Sun, Valentina Baena, Zulfeqhar A. Syed, Elizabeth Murphy, Brian Glancy, Nicolai P. Ostberg, Bruno B. Queliconi, Juliane C. Campos, Julio C. B. Ferreira, Bereketeab Haileselassie, Daria Mochly-Rosen
Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia–reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury. Elezaby et al. show that cardiac troponin I interacts with mitochondrial ATP synthase to increase ATPase activity. Disrupting this interaction reduces cardiac damage following transient ischemia.
心肌肌钙蛋白 I（cTnI）是心肌细胞收缩的关键调节因子。然而，它在线粒体中的作用尚不清楚。在这里，我们发现 cTnI 定位于心脏线粒体，在非心脏细胞中稳定表达时会抑制线粒体功能，并在氧化应激下增加线粒体通透性转换孔的开放。cTnI 与 F1FO-ATP 合成酶的直接、特异和饱和结合在体外使用免疫捕获的 ATP 合成酶得到了证实，在细胞中使用近接试验也得到了证实。合理设计的多肽 P888 可抑制 cTnI 与 ATP 合成酶的结合，抑制体外 cTnI 诱导的 ATP 酶活性的增加，并减轻体内短暂缺血后的心脏损伤。我们认为，cTnI 与 ATP 合成酶结合会导致 ATP 水平降低，在心脏缺血再灌注过程中释放这种相互作用可能会增加功能线粒体库，从而减轻心脏损伤。Elezaby 等人的研究表明，心肌肌钙蛋白 I 与线粒体 ATP 合成酶相互作用，增加 ATP 酶的活性。破坏这种相互作用可减少短暂缺血后的心脏损伤。
{"title":"Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart","authors":"Aly Elezaby, Amanda J. Lin, Vijith Vijayan, Suman Pokhrel, Benjamin R. Kraemer, Luiz R. G. Bechara, Isabel Larus, Junhui Sun, Valentina Baena, Zulfeqhar A. Syed, Elizabeth Murphy, Brian Glancy, Nicolai P. Ostberg, Bruno B. Queliconi, Juliane C. Campos, Julio C. B. Ferreira, Bereketeab Haileselassie, Daria Mochly-Rosen","doi":"10.1038/s44161-024-00512-1","DOIUrl":"10.1038/s44161-024-00512-1","url":null,"abstract":"Cardiac troponin I (cTnI) is a key regulator of cardiomyocyte contraction. However, its role in mitochondria is unknown. Here we show that cTnI localized to mitochondria in the heart, inhibited mitochondrial functions when stably expressed in noncardiac cells and increased the opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific and saturable binding of cTnI to F1FO-ATP synthase was demonstrated in vitro using immune-captured ATP synthase and in cells using proximity ligation assay. cTnI binding doubled ATPase activity, whereas skeletal troponin I and several human pathogenic cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally designed peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activity in vitro and reduced cardiac injury following transient ischemia in vivo. We suggest that cTnI-bound ATP synthase results in lower ATP levels, and releasing this interaction during cardiac ischemia–reperfusion may increase the reservoir of functional mitochondria to reduce cardiac injury. Elezaby et al. show that cardiac troponin I interacts with mitochondrial ATP synthase to increase ATPase activity. Disrupting this interaction reduces cardiac damage following transient ischemia.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"987-1002"},"PeriodicalIF":9.4,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141824819","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 : 2024-07-17DOI: 10.1038/s44161-024-00513-0
Susanne Sattler, Senka Ljubojevic-Holzer
Doxorubicin treatment is a mainstay of cancer therapy but causes potent cardiotoxicity that exposes cancer survivors to the risk of heart failure. A study now identifies CD8+ T cells of the adaptive immune system as major culprits in the development of doxorubicin-induced cardiomyopathy and heart failure.
多柔比星治疗是癌症治疗的主要方法，但会引起强烈的心脏毒性，使癌症幸存者面临心力衰竭的风险。现在的一项研究发现，适应性免疫系统的 CD8+ T 细胞是导致多柔比星诱发心肌病和心力衰竭的罪魁祸首。
{"title":"CD8+ T cells as the missing link between doxorubicin cancer therapy and heart failure risk","authors":"Susanne Sattler, Senka Ljubojevic-Holzer","doi":"10.1038/s44161-024-00513-0","DOIUrl":"10.1038/s44161-024-00513-0","url":null,"abstract":"Doxorubicin treatment is a mainstay of cancer therapy but causes potent cardiotoxicity that exposes cancer survivors to the risk of heart failure. A study now identifies CD8+ T cells of the adaptive immune system as major culprits in the development of doxorubicin-induced cardiomyopathy and heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"890-892"},"PeriodicalIF":9.4,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141830349","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 : 2024-07-17DOI: 10.1038/s44161-024-00507-y
Abraham L. Bayer, Maria A. Zambrano, Sasha Smolgovsky, Zachary L. Robbe, Abul Ariza, Kuljeet Kaur, Machlan Sawden, Anne Avery, Cheryl London, Aarti Asnani, Pilar Alcaide
Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function. Bayer et al. show that CD8+ T cells contribute to the adverse cardiac effect of doxorubicin administration, promoting fibroblast activation and inflammation through a mechanism dependent on IFNγ and the degranulation of granzyme B.
多柔比星是最常用的化疗药物，会引起剂量依赖性心脏毒性和心力衰竭。然而，我们对多柔比星引起的免疫反应了解有限。在这里，我们发现多柔比星诱发心脏损伤后，CD8+ T 细胞免疫反应异常会导致不良重塑和心肌病。对非肿瘤小鼠进行多柔比星治疗会增加循环和心脏中的 IFNγ+CD8+ T 细胞，并激活淋巴组织中的效应 CD8+ T 细胞。此外，多柔比星可促进心脏 CD8+ T 细胞浸润，多柔比星治疗小鼠的 CD8+ T 细胞耗竭可减少心脏纤维化并改善收缩功能。多柔比星治疗可诱导心脏成纤维细胞表达 ICAM-1，从而增强 CD8+ T 细胞的粘附和转化、接触依赖性 CD8+ 脱颗粒和释放颗粒酶 B。犬淋巴瘤患者和人类造血恶性肿瘤患者在接受多柔比星治疗后，循环 CD8+ T 细胞增多。在人类癌症患者中，T 细胞表达 IFNγ 和 CXCR3，血浆中 CXCR3 配体 CXCL9 和 CXCL10 的水平与收缩功能下降相关。Bayer 等人的研究表明，CD8+ T 细胞通过一种依赖于 IFNγ 和颗粒酶 B 的脱颗粒机制促进成纤维细胞活化和炎症反应，从而导致了多柔比星给药对心脏的不良影响。
{"title":"Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction","authors":"Abraham L. Bayer, Maria A. Zambrano, Sasha Smolgovsky, Zachary L. Robbe, Abul Ariza, Kuljeet Kaur, Machlan Sawden, Anne Avery, Cheryl London, Aarti Asnani, Pilar Alcaide","doi":"10.1038/s44161-024-00507-y","DOIUrl":"10.1038/s44161-024-00507-y","url":null,"abstract":"Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function. Bayer et al. show that CD8+ T cells contribute to the adverse cardiac effect of doxorubicin administration, promoting fibroblast activation and inflammation through a mechanism dependent on IFNγ and the degranulation of granzyme B.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"970-986"},"PeriodicalIF":9.4,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141828401","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 : 2024-07-12DOI: 10.1038/s44161-024-00491-3
H. Haykin, E. Avishai, M. Krot, M. Ghiringhelli, M. Reshef, Y. Abboud, S. Melamed, S. Merom, N. Boshnak, H. Azulay-Debby, T. Ziv, L. Gepstein, A. Rolls
Psychological processes have a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here we demonstrate the impact of the reward system, a brain network associated with motivation and positive expectations, on the clinical outcomes of AMI in mice. Chemogenetic activation of dopaminergic neurons in the reward system improved the remodeling processes and vascularization after AMI, leading to enhanced cardiac performance compared to controls. These effects were mediated through several physiological mechanisms, including alterations in immune activity and reduced adrenergic input to the liver. We further demonstrate an anatomical connection between the reward system and the liver, functionally manifested by altered transcription of complement component 3, which in turn affects vascularization and recovery from AMI. These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential therapeutic avenues for intervention. Haykin et al. show that activation of the brain’s reward system modulates adrenergic input to the liver and complement component 3 transcription, affecting vascularization and improving cardiac recovery after acute myocardial infarction.
{"title":"Reward system activation improves recovery from acute myocardial infarction","authors":"H. Haykin, E. Avishai, M. Krot, M. Ghiringhelli, M. Reshef, Y. Abboud, S. Melamed, S. Merom, N. Boshnak, H. Azulay-Debby, T. Ziv, L. Gepstein, A. Rolls","doi":"10.1038/s44161-024-00491-3","DOIUrl":"10.1038/s44161-024-00491-3","url":null,"abstract":"Psychological processes have a crucial role in the recovery from acute myocardial infarction (AMI), yet the underlying mechanisms of these effects remain elusive. Here we demonstrate the impact of the reward system, a brain network associated with motivation and positive expectations, on the clinical outcomes of AMI in mice. Chemogenetic activation of dopaminergic neurons in the reward system improved the remodeling processes and vascularization after AMI, leading to enhanced cardiac performance compared to controls. These effects were mediated through several physiological mechanisms, including alterations in immune activity and reduced adrenergic input to the liver. We further demonstrate an anatomical connection between the reward system and the liver, functionally manifested by altered transcription of complement component 3, which in turn affects vascularization and recovery from AMI. These findings establish a causal connection between a motivational brain network and recovery from AMI, introducing potential therapeutic avenues for intervention. Haykin et al. show that activation of the brain’s reward system modulates adrenergic input to the liver and complement component 3 transcription, affecting vascularization and improving cardiac recovery after acute myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"841-856"},"PeriodicalIF":9.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639678","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 : 2024-07-12DOI: 10.1038/s44161-024-00497-x
Dylan C. Sarver, Aldons J. Lusis
Myocardial infarction can damage the heart muscle and lead to heart failure. Research on recovery typically focuses on infiltrating immune cells, damaged cardiomyocytes, over-stimulated fibroblasts and changes in vasculature. Haykin et al. now describe a multi-organ circuit linking these entities, including the brain and liver, in the repair process.
{"title":"Linking the brain to recovery after myocardial infarction","authors":"Dylan C. Sarver, Aldons J. Lusis","doi":"10.1038/s44161-024-00497-x","DOIUrl":"10.1038/s44161-024-00497-x","url":null,"abstract":"Myocardial infarction can damage the heart muscle and lead to heart failure. Research on recovery typically focuses on infiltrating immune cells, damaged cardiomyocytes, over-stimulated fibroblasts and changes in vasculature. Haykin et al. now describe a multi-organ circuit linking these entities, including the brain and liver, in the repair process.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"780-781"},"PeriodicalIF":9.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639675","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 : 2024-07-09DOI: 10.1038/s44161-024-00495-z
Amit Prabhakar, Rahul Kumar, Meetu Wadhwa, Prajakta Ghatpande, Jingkun Zhang, Ziwen Zhao, Carlos O. Lizama, Bhushan N. Kharbikar, Stefan Gräf, Carmen M. Treacy, Nicholas W. Morrell, Brian B. Graham, Giorgio Lagna, Akiko Hata
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving vascular remodeling in PVOD. Here we show that administration of MMC in rats mediates activation of protein kinase R (PKR) and the integrated stress response (ISR), which leads to the release of the endothelial adhesion molecule vascular endothelial (VE) cadherin (VE-Cad) in complex with RAD51 to the circulation, disruption of endothelial barrier and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates VE-Cad depletion, elevation of vascular permeability and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygous BMPR2 mutation that truncates the carboxyl tail of the receptor BMPR2, underscoring the role of deregulated bone morphogenetic protein signaling in the development of PVOD. Prabhakar et al. demonstrate in rats with mitomycin C-caused pulmonary veno-occlusive disease activation of protein kinase R (PKR) and the integrated stress response (ISR), leading to the depletion of VE-cadherin and RAD51 from endothelial junctions, endothelial barrier disruption and vascular remodeling. Inhibiting the PKR–ISR axis protects against mitomycin C-induced endothelial damage.
{"title":"Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response","authors":"Amit Prabhakar, Rahul Kumar, Meetu Wadhwa, Prajakta Ghatpande, Jingkun Zhang, Ziwen Zhao, Carlos O. Lizama, Bhushan N. Kharbikar, Stefan Gräf, Carmen M. Treacy, Nicholas W. Morrell, Brian B. Graham, Giorgio Lagna, Akiko Hata","doi":"10.1038/s44161-024-00495-z","DOIUrl":"10.1038/s44161-024-00495-z","url":null,"abstract":"Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving vascular remodeling in PVOD. Here we show that administration of MMC in rats mediates activation of protein kinase R (PKR) and the integrated stress response (ISR), which leads to the release of the endothelial adhesion molecule vascular endothelial (VE) cadherin (VE-Cad) in complex with RAD51 to the circulation, disruption of endothelial barrier and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates VE-Cad depletion, elevation of vascular permeability and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygous BMPR2 mutation that truncates the carboxyl tail of the receptor BMPR2, underscoring the role of deregulated bone morphogenetic protein signaling in the development of PVOD. Prabhakar et al. demonstrate in rats with mitomycin C-caused pulmonary veno-occlusive disease activation of protein kinase R (PKR) and the integrated stress response (ISR), leading to the depletion of VE-cadherin and RAD51 from endothelial junctions, endothelial barrier disruption and vascular remodeling. Inhibiting the PKR–ISR axis protects against mitomycin C-induced endothelial damage.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"799-818"},"PeriodicalIF":9.4,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639670","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 : 2024-07-08DOI: 10.1038/s44161-024-00506-z
Siyu Tian, Paul C. Evans
In response to high fluid shear stress, KLF2-mediated induction of the BMP inhibitor BMPER improves outward arterial remodeling. This knowledge is translated into a preclinical model showing that BMP9 and BMP10 neutralizing antibodies enhance flow recovery and arterialization in ischemia in diabetic mice.
{"title":"BMPER regulates arterial adaptation to flow","authors":"Siyu Tian, Paul C. Evans","doi":"10.1038/s44161-024-00506-z","DOIUrl":"10.1038/s44161-024-00506-z","url":null,"abstract":"In response to high fluid shear stress, KLF2-mediated induction of the BMP inhibitor BMPER improves outward arterial remodeling. This knowledge is translated into a preclinical model showing that BMP9 and BMP10 neutralizing antibodies enhance flow recovery and arterialization in ischemia in diabetic mice.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"777-779"},"PeriodicalIF":9.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639667","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 : 2024-07-08DOI: 10.1038/s44161-024-00496-y
Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A. Schwartz
Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. Deng et al. show that endothelial cells respond to high fluid shear stress by KLF2-mediated induction of the BMP–Smad1/5 pathway inhibitor BMPER, resulting in outward vessel remodeling, and apply this knowledge to develop an approach that improves vessel remodeling in mouse models of diabetes.
{"title":"A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling","authors":"Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A. Schwartz","doi":"10.1038/s44161-024-00496-y","DOIUrl":"10.1038/s44161-024-00496-y","url":null,"abstract":"Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. Deng et al. show that endothelial cells respond to high fluid shear stress by KLF2-mediated induction of the BMP–Smad1/5 pathway inhibitor BMPER, resulting in outward vessel remodeling, and apply this knowledge to develop an approach that improves vessel remodeling in mouse models of diabetes.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"785-798"},"PeriodicalIF":9.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639682","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 : 2024-07-05DOI: 10.1038/s44161-024-00485-1
Liane Jurida, Sebastian Werner, Fabienne Knapp, Bernd Niemann, Ling Li, Dimitri Grün, Stefanie Wirth, Axel Weber, Knut Beuerlein, Christoph Liebetrau, Christoph B. Wiedenroth, Stefan Guth, Baktybek Kojonazarov, Leili Jafari, Norbert Weissmann, Stefan Günther, Thomas Braun, Marek Bartkuhn, Ralph T. Schermuly, Peter Dorfmüller, Xiaoke Yin, Manuel Mayr, M. Lienhard Schmitz, Laureen Czech, Klaus-Dieter Schlüter, Rainer Schulz, Susanne Rohrbach, Michael Kracht
The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans. Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.
{"title":"A common gene signature of the right ventricle in failing rat and human hearts","authors":"Liane Jurida, Sebastian Werner, Fabienne Knapp, Bernd Niemann, Ling Li, Dimitri Grün, Stefanie Wirth, Axel Weber, Knut Beuerlein, Christoph Liebetrau, Christoph B. Wiedenroth, Stefan Guth, Baktybek Kojonazarov, Leili Jafari, Norbert Weissmann, Stefan Günther, Thomas Braun, Marek Bartkuhn, Ralph T. Schermuly, Peter Dorfmüller, Xiaoke Yin, Manuel Mayr, M. Lienhard Schmitz, Laureen Czech, Klaus-Dieter Schlüter, Rainer Schulz, Susanne Rohrbach, Michael Kracht","doi":"10.1038/s44161-024-00485-1","DOIUrl":"10.1038/s44161-024-00485-1","url":null,"abstract":"The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans. Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"819-840"},"PeriodicalIF":9.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00485-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639668","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 : 2024-07-05DOI: 10.1038/s44161-024-00502-3
Michael P. Lazaropoulos, Andrew A. Gibb, Douglas J. Chapski, Abheya A. Nair, Allison N. Reiter, Rajika Roy, Deborah M. Eaton, Kenneth C. Bedi Jr, Kenneth B. Margulies, Kathryn E. Wellen, Conchi Estarás, Thomas M. Vondriska, John W. Elrod
Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY–SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis. Elrod and colleagues reveal the role of ATP-citrate lyase in myofibroblast differentiation and cardiac fibrosis.
{"title":"Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program","authors":"Michael P. Lazaropoulos, Andrew A. Gibb, Douglas J. Chapski, Abheya A. Nair, Allison N. Reiter, Rajika Roy, Deborah M. Eaton, Kenneth C. Bedi Jr, Kenneth B. Margulies, Kathryn E. Wellen, Conchi Estarás, Thomas M. Vondriska, John W. Elrod","doi":"10.1038/s44161-024-00502-3","DOIUrl":"10.1038/s44161-024-00502-3","url":null,"abstract":"Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY–SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis. Elrod and colleagues reveal the role of ATP-citrate lyase in myofibroblast differentiation and cardiac fibrosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"869-882"},"PeriodicalIF":9.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00502-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639650","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}
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