Abstract 185: Tripartite Motif E3 Ubiquitin Ligase Family Proteins Regulate Intracellular Signaling During the Progression of Heart Failure

Abstract

Heart failure is a major complication of cardiovascular disease that frequently involves initial cardiac hypertrophy that provides transient compensation for decreased heart function. Eventually, decompensation leads to compromised cardiac structure and progression into heart failure. Investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K) and Akt (Protein Kinase B). MG53, a tripartite motif (TRIM) protein family member designated as TRIM72, is highly expressed in skeletal and cardiac muscle and is known to have cardioprotective effects through modulation of PI3K signaling mechanisms. It is essential for the activation of PI3K-mediated intracellular signaling in cardiomyocytes and TRIM72 overexpression is sufficient to induce PI3K signaling. As TRIM72 regulates PI3K signaling it may play a role in regulation of heart failure, which is supported by our findings that TRIM72 levels increase in the failing mouse heart. Our recent studies also show that TRIM72 can form heterodimers with other members of the TRIM family proteins that contains approximately 70 different members in the human genome. Many TRIM family proteins are known to act as E3 ubiquitin ligases that target the ubiquitin proteasome to particular proteins. Through this activity, TRIM72 homodimers and heterodimers can resolve specific substrates that can modulate aspects of the PI3K/Akt signaling cascade. Our recent studies have resolved multiple binding partners for TRIM72 in the TRIM family that are co-regulated during heart failure. Resolving the target substrates of the heterodimers formed by these various family members and determining their role in regulating PI3K/Akt signaling mechanisms during cardiac hypertrophy will be further defined as our studies continue.