Abstract 1386: TRB3 Function in Cardiac Endoplasmic Reticulum Stress
TRB3 is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 is reported to inhibit the activity of Akt protein kinases, the ATF4 and CHOP transcription factors, and the NF-κβ pathway through p65/RelA. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation or endoplasmic reticulum stress promotes TRB3 expression in non-cardiac cells. We examined TRB3 expression and function in cultured cardiomyocytes and in mouse heart. TRB3 is expressed in cultured H9C2 cardiomyocytes and also in cultured primary adult mouse cardiomyocytes. Agents that induce ER stress, including thapsigargin, palmitate, and tunicamycin, all increased TRB3 expression in cultured cardiomyocytes. Agents that increased TRB3 expression blocked growth factor-stimulated Akt activation in these cells. Knockdown of TRB3 in cultured cardiomyocytes by siRNA reversed the effects of ER stress on insulin signaling. Transverse aortic constriction surgery led to increased TRB3 expression in murine heart tissue. Transgenic mice with cardiac-specific overexpression of TRB3 were generated and were found to be viable and fertile, but they exhibited altered cardiac metabolism with reduced cardiac glucose oxidation rates. These results demonstrate that TRB3 induction is a critical aspect of the ER stress response in cardiomyocytes and that TRB3 modulates cardiac glucose metabolism.