Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after 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。的 心脏损伤后，心脏细胞群发生了显著变化，最初是中性粒细胞浸润， 巨噬细胞和成纤维细胞和内皮细胞的稳健增殖。细胞间的串扰无疑 影响心脏伤口愈合，但关于细胞间串扰是否可以靶向 促进心脏修复在这个建议中，我们确定了一个不寻常的串扰之间的肌细胞和非- 调节心脏伤口愈合的肌细胞。我们证明了心脏成纤维细胞 在缺血性心脏损伤后上调蛋白ENPP 1（外核苷酸焦磷酸酶1）。ENPP1 水解细胞外ATP，我们发现ATP水解产物诱导心肌细胞释放 促炎并诱导各种调节伤口的非肌细胞的细胞死亡的代谢物 愈合，例如巨噬细胞、内皮细胞、成纤维细胞和平滑肌细胞。我们发现这样的 肌细胞分泌的促炎代谢物，并研究这种作用的分子机制 非肌细胞上的代谢物。我们提供的初步数据表明，ENPP 1基因缺失可能与心肌梗死相关。 成纤维细胞显著改善损伤后心脏功能，并与减少瘢痕形成有关， 减少损伤后心脏扩张。我们鉴定了ENPP 1的小分子抑制剂以及单克隆抑制剂。 靶向ENPP 1的抗体，并证明ENPP 1的药理学靶向可以作为 梗死后心脏重塑的治疗策略。这些观察结果构成了一个合理的基础， 深入研究ENPP 1介导的肌细胞-非肌细胞串扰的生理意义， 心脏修复和确定ENPP 1介导的成纤维细胞-非心肌细胞的药理学靶向是否 串扰是缺血性心脏损伤的潜在治疗策略。

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.