Elucidating the Role of Death Receptor 5 in the Heart

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Heart failure is a leading cause of morbidity and mortality worldwide. Cardiomyocyte survival and death play a crucial role in the pathogenesis of heart failure due to the limited capacity of cardiomyocytes to proliferate or repair. Recently, multiple clinical studies have identified TNF-related apoptosis inducing ligand (TRAIL) and its receptor, death receptor 5 (DR5), as being two of the most powerful predictive markers of heart failure development and severity. Additionally, whole transcriptome analysis from our laboratory identified TRAIL and DR5 alterations in a mouse model of heart failure and its involvement in cardioprotective, EGFR-dependent signaling. While there have been multiple studies demonstrating high expression of TRAIL and DR5 in the heart, their function has never been investigated. The role of TRAIL/DR5 in cancer has been extensively studied due to the ability of TRAIL to selective induce apoptosis in cancer cells, however, in non-transformed cell types, the function of TRAIL/DR5 is unclear. Due to the connection of TRAIL/ DR5 with heart failure and unidentified role of TRAIL/DR5 in the heart we have been exploring the impact of DR5 signaling in cardiomyocytes. Using pharmacological agonists of DR5, we observe that DR5 activation does not induce canonical death receptor signaling pathways in cardiomyocytes but activates the pro-growth and survival kinase ERK1/2. Using specific inhibitors for signal transduction pathways, we observe that ERK1/2 activation involves the transactivation of EGFR and results in cardiomyocyte hypertrophy. Therefore, we hypothesize that DR5 activation in cardiomyocytes plays a non-canonical, cardioprotective role through the activation of pro- growth and survival mechanisms. Completion of the following research proposal will contribute important information to this novel field of study through the identification of the function and signaling mechanisms initiated by DR5 activation in cardiomyocytes, the role of DR5 in the normal and failing heart and the determination of the potential of targeting TRAIL/DR5 as a therapeutic strategy in heart failure.