Heart failure accounts for substantial morbidity and mortality worldwide. Accumulating evidence suggests that aberrant cardiac cell death caused by endoplasmic reticulum stress (ERS) is often associated with structural or functional cardiac abnormalities that lead to insufficient cardiac output. The detailed molecular mechanism underlying the pathological death of cardiomyocytes still remains poorly understood. We found that 17-AAG (tanespimycin), an HSP90 (heat shock protein 90) inhibitor often used to kill cancer cells, could potently inhibit tunicamycin-induced ERS and the downstream nuclear factor kappa B activity in neonatal rat cardiomyocytes, leading to diminished apoptotic signaling and thus enhanced cell survival. Interestingly, the antiapoptotic effect of 17-AAG on cardiomyocytes required normal expression of miR-93, an oncogenic microRNA known to promote cell survival and growth. Our study implicated a new pharmacological role of 17-AAG in supporting the miR-93-associated oncogenic signaling to prevent the pathological death of cardiomyocytes. The results opened opportunities for exploring new strategies in the development of therapeutic agents.
Keywords: 17-AAG; HSP90; cardiomyocytes; miR-93.
© 2018 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.