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：
10471907
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/10471907
关键词：
Acute Affect Animals Area Attenuated Biochemical Cardiac Cardiac Myocytes Cardiovascular system Cell Death 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 Mediating Mediator of activation protein Metabolic Molecular Molecular Mechanisms of Action Monoclonal Antibodies Muscle Cells Myocardial Infarction Myocardial dysfunction Myocardium Natural regeneration Necrosis Nuclear Magnetic Resonance Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology 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 heart function hemodynamics injured ischemic injury loss of function macrophage metabolomics monocyte myocardial injury neutrophil novel plasma cell membrane glycoprotein PC-1 preservation pyrophosphatase repair function 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.

项目摘要/摘要心脏心肌损伤后心脏修复涉及一组精心策划的细胞事件。这心脏细胞群体在心脏损伤后随着最初嗜中性粒细胞的渗透而大大变化，然后巨噬细胞和成纤维细胞和内皮细胞的鲁棒增殖。毫无疑问影响心脏伤口愈合，但对于是否可以针对细胞 - 细胞串门对话知之甚少增强心脏修复。在此提案中，我们确定了肌细胞与非 - 调节心脏伤口愈合的心肌细胞。我们证明心脏成纤维细胞急剧缺血性心脏损伤后，上调蛋白质ENPP1（Ecton核苷酸焦磷酸酶1）。 ENPP1 水解细胞外ATP，我们表明ATP水解产物诱导肌细胞释放促炎和诱导各种非肌细胞细胞的细胞死亡的代谢产物调节伤口的细胞死亡愈合，例如巨噬细胞，内皮细胞，成纤维细胞和平滑肌细胞。我们确定了这一点心肌分泌的促炎性代谢物并研究了这种作用的分子机制非肌细胞细胞上的代谢产物。我们提供了遗传缺失ENPP1在心脏中的初步数据成纤维细胞极大地改善了损伤后心脏功能，并与疤痕减少和损伤后心脏扩张减少。我们鉴定ENPP1和单克隆的小分子抑制剂靶向ENPP1的抗体并证明了ENPP1的药理学靶向可以用作梗塞后心脏重塑的治疗策略。这些观察构成了合理的基础深入研究ENPP1介导的肌细胞 - 非心肌交叉的生理意义心脏修复并确定ENPP1介导的成纤维细胞非肌细胞的药理靶向是否串扰可能是缺血性心脏损伤的治疗策略。