The cardioprotective effects of Empagliflozin in Doxorubicin-induced endoplasmic reticulum (ER) stress

The use of doxorubicin (Dox) in cancer patients carries the risk of cardiotoxicity which is associated with an excessive production of reactive oxygen species as well as an imbalance in the redox state affecting mitochondrial functioning, ER homeostasis and protein folding. An accumulation of misfolded proteins triggers the unfolded protein response (UPR) known as ER stress. Subsequently ER-stress induced apoptosis results in loss of cardiomyocytes. Despite clinical trials indicating the benefits of an antidiabetic drug, Empagliflozin (EMPA) in reducing cardiovascular deaths and hospitalization rate in heart failure patients, it remains uncertain whether EMPA exerts a cardioprotective effect on Dox-induced cardiomyopathy (DIC). Herein, we aimed to investigate the effects of EMPA on Dox-induced ER stress and cardiomyopathy. In isolated adult rat cardiomyocytes, Dox (10μM, 24hrs) induced oxidative stress causing the activation of inflammation markers as well as ER-stress markers. Interestingly, EMPA (500nM, 24hrs) treatment prior to Dox was able to reduce oxidative stress; inflammatory markers (IL-1β, TNFα, and TGFβ), and significantly increased the expression of STAT-3. Dox-induced ER-stress activated ER transmembrane proteins and upregulated the expression of various genes, including X-box binding protein 1 (XBP1). The splicing of XBP1 mRNA on Dox treatment generated spliced XBP1 and subsequently up-regulated chaperones like glucose regulated protein 94 (GRP94), glucose regulated protein 78 (GRP78), and/or protein disulfide-isomerase (PDI). These Dox-induced changes in the upregulation of ER stress proteins were blunted by EMPA. EMPA also promoted expression of inositol requiring kinase 1α (IRE1α) which helped in maintaining ER homeostasis. Additionally, EMPA treatment, down-regulated caspase-12 and caspase-3 activation as well as phosphorylation of c-JUN NH2-terminal kinase (JNK), thereby promoting cardiomyocyte survival. These cardioprotective effects of EMPA on the reduction of ER stress in an in-vitro DIC model suggests its therapeutic potential that can occur independent of the effects related to diabetes. Thus, EMPA may contribute to improvements in cardiac damage during Dox mediated stress and inflammation. The recognition of Dox-induced cardiotoxicity as well as a dire need for a cardioprotective agent to be administered in conjunction with Dox is evident and EMPA may prove to be such an agent. Supported by CANUSA grant. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.