Abstract 16723: The MER Tyrosine Kinase Limits Apoptotic Cell Accumulation in the Heart and Attenuates Ventricular Dysfunction Post Myocardial Infarction
Post myocardial infarction (MI), phagocytes are recruited to the heart to promote tissue repair and phagocytic clearance of necrotic and apoptotic cells. The molecular pathways required for apoptotic cell clearance (efferocytosis) in the heart are unknown, as well as if efferocytosis per se affects ventricular remodeling and cardiac function. MERTK is a receptor for apoptotic cells that is expressed on the surface of recruited macrophage phagocytes. Previously we showed that MERTK is required for efferocytosis and reduced apoptotic cell accumulation in atherosclerosis. Given the evidence that clearance pathways are linked to resolution of inflammation and ensuing tissue repair, we hypothesized that the efficiency of efferocytosis post MI contributes to the extent of subsequent heart repair. To test this, control and Mertk deficient mice were subjected to MI by ligation of the left anterior descending (LAD) coronary artery. In control animals, we discovered that Mertk mRNA and protein levels were significantly elevated in the heart post LAD ligation. By flow cytometry, MERTK protein was also detected on the surface of newly recruited F4/80+ phagocyte subsets. Relative to control, whole body Mertk knockout and myeloid Mertk deficiency from bone marrow chimeras, led to increased accumulation of TUNEL positive apoptotic cells (2.4+/-0.3% vs 4.5+/-0.7% in chimeras, p<0.01) in infarct border zones. In addition, TNFα and IL-6 levels were elevated in knockouts while IL-10 was reduced. Initial infarct sizes as a percentage of ischemic area at risk were similar between both groups. However, infarct size in Mertk-/- mice subsequently expanded signficantly relative to control. At later time points, hearts from Mertk-/- mice had elevated scarring and ventricular wall thinning by histology. Echocardiography indicated that Mertk-/- hearts displayed significantly exaggerated LV dysfunction, including reduced ejection fraction. Taken together, these findings suggest that efferocytosis pathways have the capacity to regulate cardiac remodeling and heart function after a heart attack. Strategies that target optimal dead cell clearance and associated inflammation resolution and repair pathways may be of benefit in helping to heal the heart. .
- © 2012 by American Heart Association, Inc.