Abstract 63: MerTK and Mfge8-Dependent Efferocytosis Orchestrates Postischemic Cardiac Healing Through VEGF-A and Il-10 Regulation

Abstract

Inflammation orchestrates tissue remodeling after myocardial infarction (MI). Efferocytosis is mainly carried out by the membrane protein tyrosin kinase mertk (MerTK) and the milk fat globule epidermal growth factor (Mfge8) and may balance inflammation resolution after MI. We reasoned that efficient MerTK and Mfge8-dependent clearance of apoptotic debris by infiltrated myeloid cells is critical to the angiogenic and regenerative fine-tuning of the ischemic cardiac tissue. We first demonstrated that the left ventricle ejection fraction assessed by echocardiography and the number of capillaries were decreased by around 1.5-fold in MerTK -/-, Mfge8 -/- and double deficient mice when compared to wild-type animals (WT), 14 days after the onset of ischemia (p<0.01, n=10 per group). These effects were associated with an increased infarct size, fibrotic area as well as apoptotic cells number and were also observed in irradiated WT mice transplanted with bone marrow-derived cells isolated from MerTK -/-, Mfge8 -/- and double deficient animals. In cardiac tissue of WT CD45.1 recipient mice, the number of infiltrated CD45.2 MerTK -/-/Mfge8 -/- bone marrow-derived cells was similar to that of CD45.2 WT cells. In addition, the amount of Ly6Chigh and Ly6Clow monocytes as well as that of macrophages was unaffected in infarcted heart of MerTK -/-/Mfge8 -/- bone-marrow transplanted compared to WT mice. In contrast, deficient efferocytosis was related to an increased number of cardiac annexinV-positive microparticles and a downregulation of the pro-angiogenic growth factor VEGF-A and the anti-inflammatory cytokine IL-10 protein levels. Notably, FACS-sorted Ly6Clow monocytes from ischemic cardiac tissue of MerTK -/-/Mfge8 -/- mice expressed lower levels of VEGF-A when compared to WT cells. Hence, inhibition of efferocytosis leads to an adverse cardiac remodeling after MI through phenotypic alterations of phagocytic cells.