Abstract 12632: Death Receptor 5 Contributes to Cardiomyocyte Hypertrophy and Survival Through Non-Canonical Mechanisms

IntroductionA common characteristic and main contributor to most cardiac diseases is cardiomyocyte death. Apoptosis, a major contributor to cardiomyocyte death, acts through the intrinsic pathway, which has been extensively studied, and the extrinsic pathway, some of which have been well characterized. However, numerous death receptors (DR) have been virtually unstudied in the context of cardiovascular disease. Our laboratory identified TNF-related apoptosis inducing ligand (TRAIL) and its receptor, DR5, as being altered in a chronic catecholamine administration model of heart failure. Furthermore, multiple clinical studies have identified TRAIL or DR5 as biomarkers in the prediction of severity and mortality following myocardial infarction and in heart failure development risk. While TRAIL/DR5 have been extensively studied as a potential cancer therapeutic due to their ability to selectively activate apoptosis in cancer cells, TRAIL and DR5 are highly expressed in the heart where their function is unknown.HypothesisOur goal was to determine the role of DR5 in the heart and we hypothesized that DR5 initiates non-canonical signaling resulting activation of pro-growth and survival pathways, which helps protect the heart during injury.Methods/ResultsHistological analysis of hearts from mice treated with a DR5 agonists showed no difference in cardiomyocyte death, fibrosis or function as measured by echocardigraphy, but increased hypertrophy. Studies using isolated cardiomyocytes identified ERK1/2 activation with DR5 agonist treatment. Furthermore, epidermal growth factor receptor (EGFR) was activated following DR5 agonist treatment through activation of MMP9. Specific inhibitors of MMP9 and EGFR prevented DR5-mediated ERK1/2 signaling and cardiomyocyte hypertrophy. Using an in vitro hypoxia/reoxygenation model, DR5 activation was found to protect cardiomyocytes from death and DR5 agonist administration in mice decreased infarct size and improved cardiac function following ischemia/reperfusion injury. Furthermore, administration of DR5 neutralizing antibodies potentiated cardiomyocyte death following ischemia/reperfusion and worsened outcome.ConclusionsTaken together, these studies identify a previously unidentified role for DR5 in the heart, which acting through non-canonical MMP9-EGFR-ERK1/2 signaling mechanisms contributes to cardiomyocyte hypertrophy and protection from oxidative stress.