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

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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.