Abstract 792: Core Cell Survival Requirements of Hypoxia Inducible Factors in Macrophages Dominate Isoform-Specific Function during Cardiac Repair

Abstract

Objective: Hypoxia inducible factors (HIF) regulate the adaptive response to ischemic injury and enhancement of HIF levels has been proposed as a therapeutic target to improve tissue repair after acute myocardial infarction (MI). HIFs also regulate the inflammatory function of macrophages, the main protagonists of tissue repair after MI, but it is unknown whether changes in macrophage HIF levels will affect outcomes after MI. Using a murine model of acute MI and conditional knockouts, we investigated a role for macrophage HIFs in tissue repair after MI. Methods and Results: In mice subjected to permanent occlusion MI, we observed an accumulation of hypoxic cardiac macrophages and sequential stabilization of HIF-2α followed by HIF-1α, which persisted into the development of heart failure. In patients with ischemic cardiomyopathy, flow cytometry and single-cell transcriptomics revealed a parallel stabilization of HIFs and hypoxia signaling in cardiac macrophages. Since HIFs were stabilized early after MI in cardiac macrophages, we selectively targeted macrophage HIFs using conditional knockouts. Selective deletion of macrophage HIF-2α promoted cardiac macrophage production of IL-10, activating fibroblasts and stimulating collagen deposition, culminating in improved ventricular remodeling and preservation of systolic function. Similarly, selective deletion of macrophage HIF-1α improved cardiac repair; however, this was mechanistically distinct from HIF-2α, inhibiting HIF-1α-dependent proteolytic destruction of MerTK and leading to improved efferocytosis by cardiac macrophages. Contrary to our expectations, loss of both HIF-1α and HIF-2α in hypoxic macrophages enhanced mitochondrial reactive oxygen species and activated necroptosis, leading to increased cell death and cardiac rupture after acute MI. Inhibition of necroptosis with necrostatin-1 attenuated hypoxic macrophage cell death and significantly improved survival after acute MI. Conclusions: These data imply strategies that broadly enhance or inhibit HIFs will lead to catastrophic outcomes after MI, while selective inhibition of macrophage HIF-1α or HIF-2α may enhance tissue repair, preserve systolic function, and limit progression to heart failure.