Nature cardiovascular research最新文献_第6页

APOE–NOTCH axis governs elastogenesis during human cardiac valve remodeling APOE-NOTCH 轴控制着人类心脏瓣膜重塑过程中的弹性生成

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-24 DOI: 10.1038/s44161-024-00510-3

Ziyi Liu, Yu Liu, Zhiyun Yu, Cheng Tan, Nicole Pek, Anna O’Donnell, Angeline Wu, Ian Glass, David S. Winlaw, Minzhe Guo, Jason R. Spence, Ya-Wen Chen, Katherine E. Yutzey, Yifei Miao, Mingxia Gu

{"title":"APOE–NOTCH axis governs elastogenesis during human cardiac valve remodeling","authors":"Ziyi Liu, Yu Liu, Zhiyun Yu, Cheng Tan, Nicole Pek, Anna O’Donnell, Angeline Wu, Ian Glass, David S. Winlaw, Minzhe Guo, Jason R. Spence, Ya-Wen Chen, Katherine E. Yutzey, Yifei Miao, Mingxia Gu","doi":"10.1038/s44161-024-00510-3","DOIUrl":"10.1038/s44161-024-00510-3","url":null,"abstract":"Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE)+, elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell–cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1–NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling. Z. Liu, Y. Liu and Z. Yu et al. discovered a subtype of valve interstitial cells underneath the valve endothelial cells sensing unidirectional flow. These cells express high levels of APOE, which is responsible for JAG1–NOTCH2-mediated fetal elastogenesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"933-950"},"PeriodicalIF":9.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980504","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}

引用次数: 0

Aficamten reduces cardiac contractility by modifying the actomyosin interaction 阿菲康坦通过改变肌动蛋白的相互作用降低心脏收缩力

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-23 DOI: 10.1038/s44161-024-00503-2

Farid Moussavi-Harami, Michael Regnier

引用次数: 0

Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy Aficamten 是一种小分子心肌酶抑制剂，旨在治疗肥厚型心肌病

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-23 DOI: 10.1038/s44161-024-00505-0

James J. Hartman, Darren T. Hwee, Julien Robert-Paganin, Chihyuan Chuang, Eva R. Chin, Samantha Edell, Ken H. Lee, Roshni Madhvani, Preeti Paliwal, Julien Pernier, Saswata Sankar Sarkar, Julia Schaletzky, Kristine Schauer, Khanha D. Taheri, Jingying Wang, Eddie Wehri, Yangsong Wu, Anne Houdusse, Bradley P. Morgan, Fady I. Malik

{"title":"Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy","authors":"James J. Hartman, Darren T. Hwee, Julien Robert-Paganin, Chihyuan Chuang, Eva R. Chin, Samantha Edell, Ken H. Lee, Roshni Madhvani, Preeti Paliwal, Julien Pernier, Saswata Sankar Sarkar, Julia Schaletzky, Kristine Schauer, Khanha D. Taheri, Jingying Wang, Eddie Wehri, Yangsong Wu, Anne Houdusse, Bradley P. Morgan, Fady I. Malik","doi":"10.1038/s44161-024-00505-0","DOIUrl":"10.1038/s44161-024-00505-0","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM. Hartman et al. use mouse models of cardiac function to show that aficamten decreases the availability of myosin heads for contraction during systole, attenuating a primary driver of hypertrophic cardiomyopathy pathophysiology.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"1003-1016"},"PeriodicalIF":9.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00505-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141814245","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}

引用次数: 0

Cardiac troponin I directly binds and inhibits mitochondrial ATP synthase with a noncanonical role in the post-ischemic heart 心肌肌钙蛋白 I 直接结合并抑制线粒体 ATP 合成酶，在缺血后心脏中发挥非典型作用

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-18 DOI: 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

{"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}

引用次数: 0

CD8+ T cells as the missing link between doxorubicin cancer therapy and heart failure risk CD8+ T 细胞是多柔比星癌症疗法与心力衰竭风险之间的缺失环节

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-17 DOI: 10.1038/s44161-024-00513-0

Susanne Sattler, Senka Ljubojevic-Holzer

引用次数: 0

Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction 细胞毒性 T 细胞驱动多柔比星诱导的心脏纤维化和收缩功能障碍

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-17 DOI: 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

{"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}

引用次数: 0

Reward system activation improves recovery from acute myocardial infarction 奖赏系统激活可改善急性心肌梗死的恢复情况

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-12 DOI: 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

{"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}

引用次数: 0

Linking the brain to recovery after myocardial infarction 将大脑与心肌梗塞后的恢复联系起来

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-12 DOI: 10.1038/s44161-024-00497-x

Dylan C. Sarver, Aldons J. Lusis

引用次数: 0

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response 通过抑制综合应激反应逆转肺静脉闭塞症表型

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-09 DOI: 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

{"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}

引用次数: 0

BMPER regulates arterial adaptation to flow BMPER 调节动脉对流量的适应性

IF 9.4

Nature cardiovascular research Pub Date : 2024-07-08 DOI: 10.1038/s44161-024-00506-z

Siyu Tian, Paul C. Evans

引用次数: 0