Abstract 419: OLA1 Regulates GSK3β/eIF2-alpha Signaling Axis in Angiotensin II-treated Human Ventricular Cardiomyocytes

Abstract

Pathological cardiac hypertrophy in response to stress or disease such as hypertension, myocardial infarction, valvular disease or neurohomonal dysregulation often result in heart failure. Cardiac hypertrophy is associated with changes in key molecular features including protein synthesis, sarcomeric organization, fibrogenesis, cell death and energy metabolism. OBG like ATPase 1 (OLA1) belongs to the translation factor-related (TRAFAC) class, Obg family, and YchF subfamily of P-loop GTPases that play a crucial role in the regulation of diverse cellular processes including protein translation, intracellular transport, signal transduction and growth. Recent study has shown that OLA1 functions as an intrinsic regulator in cellular stress responses, such as oxidative stress and heat shock. However, its role in cardiac hypertrophy is unknown so far. Here, we investigated the effect of OLA1 deficiency on angiotensin II (ANG II)-induced hypertrophic signaling response in immortalized human ventricular cardiomyocytes (hCM) and in heart tissue from OLA1 knockout mice. We observed that ANG II-induced increase in cardiomyocyte cell size was lower in OLA1 knockdown hCM cells as compared to control transfected cells. Interestingly, OLA1 knockdown inhibits the above effect and increases phosphorylation of GSK3β and eIF2α (inactive state). Furthermore, OLA1 homozygous knockout mice showed increase in phosphorylation of GSK3β. Taken together, these findings show that OLA1 deficiency decreases ANG II-induced hypertrophy signaling response in ventricular cardiomyocytes. This study provides the first evidence for the role of OLA1 in ANG II-induced hypertrophic response of human ventricular cardiomyocytes.