A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2(-/-) mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Shaanxi Provincial Key Research and Development Projects (2019SF-218) Background Endoplasmic reticulum (ER) stress played an essential role in the development and progression of HF due to it could induce cardiomyocyte apoptosis, ATF6/CHOP was regulated by NADPH and ROS and was the crucial pathway to link ER stress and apoptosis in HF. Our previous study indicated that ECH reversed cardiac remodeling and improves heart function, but the underlying mechanisms are still unclear. Objectives To investigate the effect of ECH on cardiomyocyte apoptosis and endoplasmic reticulum stress and the underlying mechanisms. Methods In vitro, we cultured AC-16 cells and induced cell damage and ER stress by ISO, treated by ECH, the cell apoptosis and biomarkers of ER stress (GRP78, ATF6α, IRE1α, PERK) were detected. In vivo, we induced HF rat model by ISO and treated by ECH, indexes of heart function, cardiomyocyte apoptosis, biomarkers of ER stress and NADPH/ROS/ATF6/CHOP pathway were measured. Results In vitro, we confirmed that ECH inhibited ER stress and apoptosis. In vivo, we demonstrated that ECH inhibited cardiomyocyte apoptosis and improved heart function, it significantly decreased GRP78, ATF6α, IRE1α, PERK, and down-regulated NADPH/ROS/ATF6/CHOP pathway. Conclusions ECH inhibited cardiomyocyte apoptosis and improved heart function via suppressing NADPH/ROS/ATF6/CHOP pathway associated ER stress.