Role of macrophages in regulating cardiac muscle metabolism

Abstract Following myocardial infarction, the heart is infiltrated in a precise spatio-temporal manner first by neutrophils and then by cells of the monocyte-macrophage lineage followed by proliferation of resident fibroblasts and endothelial cells. Cell-cell cross talk has been recently considered to be an important reparative mechanism but little is known about how the myocytes themselves engage in such cross talk with non-myocyte cells that are recruited to the infarcted region. In this proposal, we highlight and investigate an unusual cross talk between macrophages and cardiac muscle cells in the infarcted heart. We show that cardiac macrophages that are recruited to the infarcted heart disrupt cardiac muscle metabolism and lead to decreased NAD pools that play a critical role in cardiac muscle energetics in the infarcted heart. Bone marrow transplantation experiments performed by us definitively demonstrate that deletion of a NADase on macrophages leads to superior post infarct heart function and superior cardiac cellular respiration. Finally using monoclonal antibodies targeting specific NADases on macrophages, we demonstrate that specific targeting of such proteins could serve as therapeutic strategies for augmenting cardiac muscle energetics and post infarct heart function. We have created a multi-disciplinary team with expertise in cardiac metabolism, in vivo isotope labeled metabolite tracing, nucleotide biochemistry and cardiac physiology and comprehensively investigate the cellular, molecular, and metabolic underpinnings of how bone marrow macrophages regulate cardiac muscle metabolism and energetics. Our proposal sheds novel insight into the hitherto unappreciated role of how macrophages regulate cardiac muscle metabolism after heart injury.