Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.