Innate-like CD8+ T-cells facilitate in cardiac remodeling post-MI

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Regional myocardial ischemia that leads to injury and myocyte necrosis results in focal scar formation and a reduction in ventricular systolic function. The constitutive properties of the infarcted myocardium are major determinants of left ventricular remodeling. The long-term goal of the proposal is to investigate the mechanisms of cardiac healing and scar composition after myocardial infarction (MI) to provide targets and novel pathways that drive adverse cardiac remodeling and left ventricular dysfunction. The specific objective is to characterize the physiological effects of a specialized CD8+ T-cell population termed the innate-like CD8+ T-cells (ILTs) and dissect how these cells regulate cardiac scar composition and biomechanics after MI. The central hypothesis is that ILTs decrease (ECM) deposition and alter fibroblast activity via granzyme K (GzmK)-mediated paracrine signaling through protease activated receptor-1 (PAR1) leading to a less stiff scar. Aim 1 will test the hypothesis that ILTs are a fundamental determinant of the constitutive properties of ischemia induced myocardial scar and resulting changes in ventricular structure and function. Aim 2 will test the hypothesis that one mechanism by which ILTs influence scar biomechanics and LV remodeling is GzmK induced alterations in ECM degradation. Aim 3 will test the hypothesis that one mechanism by which ILTs inhibit fibroblast activation is through GzmK induced PAR1 signaling. Our proposed research targets a novel cellular, molecular mechanism that alters scar properties. Understanding this mechanism behind ILT-mediated effects on constitutive properties of ischemia induced myocardial scar will provide targets and novel pathways that drive adverse cardiac remodeling and LV dysfunction. The proposed study aligns with the mission of the VA healthcare system by providing molecular knowledge to clinical practices so that we can continue to provide exceptional health care that improves veteran health and well-being.