Precision medicine approach: Empagliflozin for diabetic cardiomyopathy in mice with aldehyde dehydrogenase (ALDH) 2 * 2 mutation, a specific genetic mutation in millions of East Asians

Abstract

A vast majority of type-2 diabetic patients (~65%) die of cardiovascular complications including heart failure (HF). In diabetic hearts, levels of 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde that is produced upon lipid peroxidation, were increased. We also demonstrated that in diabetic hearts, there is a decrease in the activity of aldehyde dehydrogenase (ALDH) 2, a primary detoxifying enzyme present in cardiac mitochondria. A single point mutation at E487K of ALDH2 in East Asians known as ALDH2 * 2 intrinsically lowers ALDH2 activity. We hypothesize that Empagliflozin (EMP), a sodium-glucose cotransporter (SGLT) 2 inhibitor, can ameliorate diabetic cardiomyopathy by decreasing hyperglycemia-mediated 4HNE protein adducts in ALDH2 * 2 mutant mice which serve as a precision medicine tool as they mimic ALDH2 * 2 carriers. We induced type-2 diabetes in 11–14 month-old male and female ALDH2 * 2 mice through a high-fat diet. Chow-fed ALDH2 * 2 mice served as controls. At the end of 4 months, we treated the diabetic ALDH2 * 2 mice with EMP (3 mg/kg/d) or its vehicle (Veh). After 2 months of EMP treatment, cardiac function was assessed by conscious echocardiography after treadmill exercise stress. EMP improved the cardiac function and running distance and duration significantly compared to Veh-treated ALDH2 * 2 diabetic mice. These beneficial effects can be attributed to the EMP-mediated decrease in cardiac mitochondrial 4HNE adducts and increase in the levels of phospho AKT, AKT, phospho Akt substrate of 160 kDa (pAS160), AS160 and GLUT-4 in the skeletal muscle tissue of the ALDH2*2 mutant diabetic mice, respectively. Finally, our data implicate EMP can ameliorate diabetic cardiomyopathy in diabetic ALDH2 * 2 mutant patients.