ER stress induces myocardial dysfunction and cardiac autophagy in Sestrin2 knockout mice

Sestrin2 is an essential regulator of the cellular adaptive response against various stresses. The endoplasmic reticulum (ER) is critical in maintaining normal cardiac function by controlling intracellular Ca²⁺ accumulation, as well as protein folding and processing. Autophagy contributes to stress-associated heart dysfunction. AMP-activated protein kinase (AMPK) is important in energy homeostasis in cardiomyocytes. However, the function of Sestrin2 (Sesn2) in ER stress-induced autophagy that induces myocardial dysfunction has not been clarified. In this study, mice and cardiac tissues were treated with tunicamycin (TN), an inducer of ER stress. We then explored the roles of Sesn2 and the AMPK pathway associated with autophagy in ER stress-induced myocardial dysfunction in mice.

Echocardiography, contractile function analysis, intracellular Ca²⁺ status, and immunoblot analysis of AMPK pathway were performed, ER stress and autophagy markers were examined.

The study revealed that ER stress caused significant heart dysfunction and cardiotoxicity in the mouse heart and cardiomyocytes. Biochemical analysis indicated enhanced cardiac autophagy mediated by ER stress and AMPK/mTOR activation. Sesn2 knockout exacerbated ER stress-related myocardial dysfunction due to the failed response of cardiac autophagy and AMPK/mTOR pathway activation. Further, pharmacological inhibition of AMPK or autophagy worsened TN-induced cardiac dysfunction.

Taken together, loss of the Sesn2 protein exacerbates ER stress-induced cardiac dysfunction through the AMPK/mTOR signaling cascade and loss of autophagy response.