Abstract 4360655: Targeting Dedicator of Cytokinesis 2 Preserves Cardiac Function by Reprogramming Post-Infarction Inflammation and Metabolism

Abstract

Myocardial infarction(MI) is a leading cause of heart failure and death. Beyond the initial ischemic insult, persistent inflammation and metabolic dysfunction critically impair recovery from the MI, highlighting the need to uncover molecular pathways that drive these maladaptive responses. Transcriptomic profiling of human and murine infarcted hearts revealed upregulation of Dedicator of Cytokinesis 2 (DOCK2), a Rac-specific GEF, linked to immune cell trafficking and inflammation, prompting investigation into its pathological role in MI. Using a murine model of MI, we found that genetic ablation of DOCK2 (DOCK2-/-) conferred significant and sustained cardioprotection. Transthoracic echocardiography revealed that DOCK2-/- mice exhibited significantly higher left ventricular ejection fraction and improved fractional shortening, along with reduced left ventricular end systolic diameter and end systolic volume, indicating preserved systolic function and attenuation of adverse ventricular remodeling. TUNEL staining demonstrated significantly reduced cardiomyocyte apoptosis in DOCK2-/- hearts, while picrosirius red staining at 28 days revealed a marked reduction in myocardial fibrosis. Mechanistically, DOCK2 deletion enhanced myocardial energetic efficiency, as indicated by increased ATP production and activation of the AMP-activated protein kinase (AMPK)–acetyl-CoA carboxylase (ACC)–carnitine palmitoyltransferase 1 (CPT1) regulatory axis, consistent with a metabolic shift away from fatty acid oxidation toward glycolysis, a pathway that yields more ATP per oxygen molecule under ischemic conditions. This reprogramming was accompanied by the upregulation of key antioxidant defenses. Transcriptomic profiling further revealed suppression of inflammatory gene signatures alongside enhanced glycolytic and angiogenic pathways. These metabolic and transcriptional changes converged to promote vascular regeneration, as evidenced by increased proliferation of CD31 endothelial cells, elevated capillary density in the infarct border zone, and enhanced microvessel formation in Matrigel plug assays. DOCK2 deletion attenuated nuclear factor kappa B activation, reduced pro-inflammatory cytokine expression, and limited infiltration of neutrophils and macrophages. Together, these findings position DOCK2 as a central regulator of the inflammatory–metabolic axis in myocardial infarction, highlighting DOCK2 as a compelling therapeutic target for cardiac repair.