Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury

靶向心脏成纤维细胞-肌细胞的串扰以增强心脏损伤后的心脏功能

基本信息

批准号：
10685568
负责人：
Arjun Deb
金额：
$ 54.6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-02 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685568
关键词：
Acute Affect Animals Area Attenuated Biochemical Cardiac Cardiac Myocytes Cardiovascular system Cell Death Cell Death Induction Cell secretion Cells Cicatrix Collaborations Data Dilatation - action Diphosphates Endothelial Cells Event Fibroblasts Fibrosis Genetic Goals Heart Heart Injuries Hour Infarction Infiltration Inflammation Inflammatory Integral Membrane Protein Macrophage Mediating Mediator Metabolic Molecular Molecular Mechanisms of Action Monoclonal Antibodies Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Natural regeneration Necrosis Nuclear Magnetic Resonance Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physiological Play Population Proliferating Proteins Public Health Research Personnel Role Signal Transduction Smooth Muscle Myocytes Structure Testing Therapeutic Time Tissues Ventricular calcification cardiac repair cell type cytokine extracellular gain of function heart function hemodynamics improved injured ischemic injury loss of function metabolomics monocyte myocardial injury neutrophil novel pharmacologic plasma cell membrane glycoprotein PC-1 preservation pyrophosphatase repaired response to injury single-cell RNA sequencing small molecule small molecule inhibitor spatiotemporal stem cells treatment strategy wound healing

项目摘要

Project Summary/Abstract Cardiac repair following ischemic myocardial injury involves a carefully orchestrated set of cellular events. The cardiac cell population substantially changes after cardiac injury with infiltration of initially neutrophils, then macrophages and robust proliferation of fibroblasts and endothelial cells. Cell-cell cross talk undoubtedly affects cardiac wound healing but little is known about whether cell-cell cross talk can be targeted for enhancing cardiac repair. In this proposal, we identify an unusual cross talk between myocytes and non- myocytes that regulates cardiac wound healing. We demonstrate that cardiac fibroblasts dramatically upregulate the protein ENPP1 (ectonucleotide pyrophosphatase 1) following ischemic cardiac injury. ENPP1 hydrolyzes extracellular ATP and we show that ATP hydrolytic products induces myocytes to release metabolites that are pro-inflammatory and induce cell death of various non-myocyte cells regulating wound healing such as macrophages, endothelial cells, fibroblasts and smooth muscle cells. We identify such myocyte secreted pro-inflammatory metabolites and investigate molecular mechanisms of action of such metabolites on non-myocyte cells. We provide preliminary data that genetic deletion of ENPP1 in cardiac fibroblasts dramatically ameliorates post injury heart function and is associated with decreased scarring and decreased post injury cardiac dilatation. We identify small molecule inhibitors of ENPP1 as well as monoclonal antibodies targeting ENPP1 and demonstrate that pharmacologic targeting of ENPP1 can serve as a therapeutic strategy for post infarction cardiac remodeling. These observations form a rational basis for investigating in depth the physiological significance of ENPP1 mediated myocyte-non myocyte cross talk in cardiac repair and determine whether pharmacologic targeting of ENPP1 mediated fibroblast-non myocyte cross talk is potentially a therapeutic strategy for ischemic cardiac injury.

项目概要/摘要缺血性心肌损伤后的心脏修复涉及一系列精心策划的细胞事件。这心脏损伤后，心肌细胞群发生显着变化，最初是中性粒细胞浸润，然后巨噬细胞以及成纤维细胞和内皮细胞的强劲增殖。细胞间的串扰无疑影响心脏伤口愈合，但对于细胞间的串扰是否可以作为治疗目标尚不清楚增强心脏修复。在这个提案中，我们发现了肌细胞和非细胞之间不寻常的串扰。调节心脏伤口愈合的肌细胞。我们证明心脏成纤维细胞显着缺血性心脏损伤后上调蛋白质 ENPP1（外核苷酸焦磷酸酶 1）。 ENPP1 水解细胞外 ATP，我们发现 ATP 水解产物诱导肌细胞释放促炎并诱导调节伤口的各种非肌细胞细胞死亡的代谢物愈合如巨噬细胞、内皮细胞、成纤维细胞和平滑肌细胞。我们识别这样的肌细胞分泌促炎代谢物并研究其作用的分子机制非肌细胞上的代谢物。我们提供了心脏中 ENPP1 基因缺失的初步数据成纤维细胞可显着改善损伤后的心脏功能，并与减少疤痕和减少疤痕相关减少损伤后心脏扩张。我们鉴定了 ENPP1 的小分子抑制剂以及单克隆抗体靶向 ENPP1 的抗体，并证明 ENPP1 的药理学靶向可以作为梗死后心脏重塑的治疗策略。这些观察形成了合理的基础深入研究 ENPP1 介导的肌细胞-非肌细胞串扰的生理意义心脏修复并确定 ENPP1 的药物靶向是否介导成纤维细胞-非肌细胞串扰可能是缺血性心脏损伤的一种治疗策略。