Abstract 18348: ATF6 and the Adaptive ER Stress Response Promotes Proliferation and Viability of Mouse Cardiac Progenitor Cells

Abstract

C-kit+ cardiac stem cells, herein called cardiac progenitor cells (CPCs), are beneficial when administered to infarcted mouse hearts. Though the mechanism of these benefits is unknown, CPC vitality likely plays a major role. Thus, investigating the factors governing CPC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart, and that SR/ER protein quality control, which includes the adaptive ER stress response, is critical for the synthesis of most secreted proteins, receptors, and contractile calcium-handling proteins. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CPCs. Accordingly, the hypothesis of this study is that ATF6 and the adaptive ER stress response are critical for optimal survival of CPCs. To address this hypothesis we compared the viabilities of mouse CPCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We found that, compared to NRVM, CPCs exhibited lower levels of adaptive ER stress response gene expression and increased cell death in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CPCs. We also found that either siRNA-mediated knock down of ATF6 or chemical inhibition of ATF6 activation with AEBSF decreased adaptive ER stress response gene expression; therefore, ATF6 is an essential component of the adaptive ER stress response in CPCs. Strikingly, ATF6 knockdown decreased CPC viability and proliferation by as much as 70%. Thus, compared to cardiac myocytes, CPCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CPCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.