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Ectonucleoside triphosphate diphosphohydrolase-1 (CD39) impacts TGF-β1 responses: Insights into cardiac fibrosis and function following myocardial infarction


Novitskaya TTatiana , Nishat SShamama , Covarrubias RRoman , Wheeler DGDebra G , Chepurko EElena , Bermeo-Blanco OOscar , Xu ZZhaobin , Baer BBradly , He HHeng , Moore SNStephanie N , Dwyer KMKaren M , Cowan PJPeter J , Su YRYan Ru , Absi TSTarek S , Schoenecker JJonathan , Bellan LMLeon M , Koch WJWalter J , Bansal SShyam , Feoktistov IIgor , Robson SCSimon C , Gao EErhe , Gumina RJRichard J . American journal of physiology. Heart and circulatory physiology. 2022 10 14; ().


Extracellular purine nucleotides and nucleosides released from activated or injured cells influence multiple aspects of cardiac physiology and pathophysiology. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39) hydrolyzes released nucleotides and thereby regulates the magnitude and duration of purinergic signaling. However, the impact of CD39 activity on post-myocardial infarction (MI) remodeling is incompletely understood. We measured the levels and activity of ecto-nucleotidases in human left ventricular samples from control and ischemic cardiomyopathy (ICM) hearts and examined the impact of ablation of Cd39 expression on post-myocardial infarction remodeling in mice. We found that human CD39 levels and activity are significantly decreased in ICM hearts (n=5) compared to Control hearts (n=5). In mice null for Cd39, cardiac function and remodeling are significantly compromised in Cd39 mice following myocardial infarction. Fibrotic markers including plasminogen activator inhibitor-1 (PAI-1) expression, fibrin deposition, alpha-smooth muscle actin (aSMA) and collagen expression are increased in Cd39 hearts. Importantly we found that transforming growth factor beta-1 (TGF-β1) stimulates ATP release and induces Cd39 expression and activity on cardiac fibroblasts, constituting an autocrine regulatory pathway not previously appreciated. Absence of CD39 activity on cardiac fibroblasts exacerbates TGF-β1 pro-fibrotic responses. Treatment with exogenous ectonucleotidase rescues this pro-fibrotic response in Cd39 fibroblasts. Together, these data demonstrate that CD39 has important interactions with TGF-β1-stimulated autocrine purinergic signaling in cardiac fibroblasts and dictates outcomes of cardiac remodeling following myocardial infarction. Our results reveal that ENTPD1 (CD39) regulates TGF-β1-mediated fibroblast activation and limits adverse cardiac remodeling following myocardial infarction.