Abstract 461: Microrna-126 Overexpression Rescues Impaired Efferocytosis in Diabetes

Abstract

Cardiac healing after myocardial ischemia requires accumulation of macrophages at the site of injury for the clearance of apoptotic/dead cardiomyocytes, a process known as efferocytosis. Effective clearance of apoptotic cells in turn results in inflammation resolution during cardiac regeneration. Diabetes accompanied by hyperglycemia is known to compromise the function of macrophages leading to impaired inflammation resolution during cardiac regeneration, wound healing, atherosclerosis and auto-immune disorders. However, the effect of diabetes on macrophage efferocytosis and molecular mechanisms involved have not been understood so far. We found miR-126 is essential for the macrophage efferocytosis of apoptotic myocytes in high glucose conditions (HG). In-vivo, miR-126 expression was reduced and, a corresponding increase in A Disintegrin And Metalloprotease 9 (ADAM9) expression was observed in human diabetic heart failure tissues compared with the normal counterparts. In-vitro, macrophages efferocytosis was reduced in HG compared to normal glucose. Over-expression of miR-126 increased the efferocytosis in HG. Mechanistically, reduced miR-126 leads to increased expression of human ADAM9. ADAM9 in turn cleaves Mer tyrosine receptor kinase (MerTK), a proto-oncogene that plays a role in efferocytosis, leading to the formation of soluble-Mer that reduces the macrophage efferocytosis in HG conditions. This, we term as “not ready to eat” signal of the macrophages, which could be rescued by overexpressing miR-126 and termed as “ready to eat” signal of the macrophages.