Explore the roles of intercellular communication in cardiomyocyte proliferation and renewal.

探索细胞间通讯在心肌细胞增殖和更新​​中的作用。

• 批准号: 10561156
• 负责人: Liang Xie
• 金额: $ 50.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561156
• 关键词: APLN gene; Adult; Aging; Animal Model; Blood Vessels; Cardiac; Cardiac Myocytes; Cells; Chronic; Communication; Cues; Data; Deterioration; Development; Disease; Endothelial Cells; Endothelium; Failure; Fibroblasts; Fibrosis; G-Protein-Coupled Receptors; Gene Expression; General Population; Heart; Heart Diseases; Heart failure; Hypoxia; Knock-out; Knockout Mice; Ligands; Mediating; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Natural regeneration; Neonatal; Nutrient; Organ Size; Oxygen; Pathologic; Pathway interactions; Patients; Peptides; Play; Population; Prevalence; Procollagen-Proline Dioxygenase; Proliferating; Proteins; Receptor Cell; Receptor Inhibition; Recovery; Regenerative capacity; Regulation; Role; Signaling Protein; Source; Tertiary Protein Structure; Testing; Therapeutic; Ventricular; Ventricular Remodeling; cardiogenesis; cell type; first responder; genetic manipulation; heart function; improved; in vivo; integrin-linked kinase; intercellular communication; mortality; mouse model; myocardial injury; new therapeutic target; novel strategies; paracrine; prevent; protein activation; receptor; sensor; single-cell RNA sequencing

ABSTRACT Heart failure (HF) is a leading cause of morbidity and mortality in the US and its prevalence is expected to rise with the aging of the general population. Myocardial infarction (MI), chronic cardiac overload or valvular diseases often lead to the loss of cardiomyocytes (CMs). However, the limited endogenous proliferation capacity of adult CM impedes CM renewal and contributes to the development of HF. Interestingly, recent studies indicate that hypoxia promotes CM proliferation and improves recovery after myocardial injury, suggesting that endogenous pathways involved in CM proliferation can be activated and are sufficient to induce CM renewal without genetic manipulation in both healthy and diseased hearts. Therefore, promotion of endogenous CM renewal is a promising therapeutic approach to treat HF. However, the mechanisms involved in hypoxia-induced CM proliferation remain largely unknown. Prolyl hydroxylase domain proteins (PHDs) are widely considered as the oxygen sensors. Whether PHDs are involved in hypoxia-induced CM proliferation and renewal is unknown. Further, endothelial cells (ECs) act as the “first-responder” to environmental cues such as oxygen and nutrients. It is unclear whether cardiac EC-CM communication plays a role in hypoxia-induced CM proliferation. Therefore, exploring the role of endothelial PHDs in CM proliferation is of critical importance for understanding the basic mechanisms involved in endogenous CM renewal and will provide us novel approaches to treat HF. We have recently demonstrated that EC-specific knockout (eKO) of PHD2/3 promoted CM proliferation, improved cardiac function, and prevented ventricular failure induced by MI. Mechanistically, we discovered that yes-associated protein (YAP), a key player of organ size control and CM proliferation, was specifically activated in CMs of PHD2/3 eKO mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that apelin (Apln), a GPCR ligand, was markedly upregulated in cardiac ECs of PHD2/3 eKO mice via HIF-2a. We further demonstrated that Apln potently activated YAP in CMs and promoted CM proliferation. Notably, deletion of HIF- 2a or Apln in ECs eliminated the beneficial effects on cardiac function observed in PHD2/3 eKO mice. More importantly, CM-specific deletion of Apln receptor (AplnR) in mice at neonatal or adult stages inhibited YAP activation and deteriorated heart function. These data lead us to hypothesize that an endothelial PHD-mediated paracrine mechanism plays a key role in CM proliferation and renewal via Apln/AplnR pathway. To test this hypothesis, we will elucidate the underlying molecular mechanism by which endothelial PHD-mediated paracrine pathways regulate Hippo-YAP signaling in CMs. In addition, we will study the essential role of Apln/AplnR pathway in CM proliferation and normal heart function. Last, we will investigate the role of Apln/AplnR pathway in mouse models of heart failure.

抽象的 心力衰竭（HF）是美国发病率和死亡率的主要原因，预计其患病率将上升 随着普通人群的老化。心肌梗塞（MI），慢性心脏超负荷或瓣膜疾病 通常导致心肌细胞（CMS）的丧失。但是，成人的内源性增殖能力有限 CM阻碍了CM续签，并有助于HF的发展。有趣的是，最近的研究表明 缺氧促进CM增殖并改善心肌损伤后的恢复，表明内源性 CM增殖涉及的途径可以激活，并且足以诱导CM更新而没有遗传 在健康和厌恶的心脏中操纵。因此，促进内源商业更新是一个 有希望治疗HF的有前途的治疗方法。但是，缺氧诱导的CM涉及的机制 增殖仍然很大程度上是未知的。丙酰羟化酶结构蛋白（PHD）被广泛认为是 氧气传感器。 PHD是否参与缺氧引起的CM增殖和更新​​是未知的。更远， 内皮细胞（ECS）充当环境线索（例如氧气和养分）的“第一反应者”。这是 尚不清楚心脏EC-CM通信是否在缺氧引起的CM增殖中起作用。所以， 探索内皮博士在CM增殖中的作用对于理解基本的作用至关重要 内源性CM更新涉及的机制，将为我们提供治疗HF的新方法。 我们最近证明了PHD2/3的EC特异性敲除（EKO）促进了CM增殖， 改善心脏功能，并防止MI诱导的心室衰竭。从机械上讲，我们发现 与器官尺寸控制和CM增殖的关键参与者是相关的蛋白质（YAP），被专门激活 在PHD2/3 EKO小鼠的CMS中。单细胞RNA测序（SCRNA-SEQ）分析表明，Apelin（APLN），A GPCR配体通过HIF-2A在PHD2/3 EKO小鼠的心脏EC中明显更新。我们进一步 证明APLN可能在CMS中可能激活YAP并促进CM增殖。值得注意的是，删除hif- ECS中的2A或APLN消除了对PHD2/3 Eko小鼠中心脏功能的有益影响。更多的 重要的是，在新生儿或成人阶段，小鼠APLN受体（APLNR）的CM特异性缺失抑制了YAP 激活和确定的心脏功能。这些数据导致我们假设内皮博士学位介导 旁分泌机制在CM增殖和通过APLN/APLNR途径更新中起关键作用。测试这个 假设，我们将阐明内皮PHD介导的旁分泌的潜在分子机制 途径调节CMS中的河马信号传导。此外，我们将研究APLN/APLNR的基本作用 CM增殖和正常心脏功能的途径。最后，我们将研究APLN/APLNR途径的作用 在鼠标模型中。