Suppression of Defender against cell death 1 leads to cardiomyocyte death
Background/Purpose】Since cardiomyocytes lose proliferative capacity soon after birth, inhibiting cardiomyocyte death is one of the important therapeutic strategies for heart failure. The goal of this study is to identify novel genes which inhibit cell death in cardiomyocytes (CMs).
【Method/Results】We found a CM death suppressing gene Dad1, whose function in the heart has not yet been elucidated. The siRNA was used to suppress the expression of Dad1 in neonatal rat CMs (NRCMs) and evaluate cell viability. As a result, suppression of Dad1 induced cell death. In addition, suppression of Dad1 increased GRP78 expression, which is an ER stress marker, suggesting ER stress is involved in cell death. In contrast, apoptosis inhibitor z-VAD-fmk failed to suppress cell death caused by suppression of Dad1. Moreover, the expression of Stt3a, a catalytic subunit of the oligosaccharyltransferase (OST) complex which Dad1 stabilizes, was suppressed, and cardiomyocyte death was also induced by suppression of Stt3a expression.
【Conclusion】 Dad1 inhibits NRCM death and ER stress and stabilizes OST complex. Thus, enhancement of Dad1 expression could be a new therapeutic target for heart failure.