Diabetic cardiomyopathy (DbCM) increases mortality and morbidity in type 2 diabetes (T2D) subjects. Increased cardiac aldose reductase (AR) activity has been correlated with impaired cardiac function and less effective energy metabolism in DbCM subjects. The aim of the present study was to evaluate the effect AT-001, a potent and selective AR inhibitor, on cardiac function, structure, and energy metabolism in diabetic cardiomyopathic mice that overexpress the human AR (hAR-Tg) . The effects of AT-001 were compared to those of dapagliflozin, a sodium-glucose cotransporter inhibitor that decreases the risk of cardiovascular death. DbCM was induced in human AR overexpressing transgenic (hAR-Tg) mice by subjecting them to a high-fat diet (60% kcal from lard) for 10-wk with a single intraperitoneal streptozotocin injection (75 mg/kg) at 4-wk. Male mice were randomized to receive either vehicle, AT-001 (40 mg/kg/day) ,or dapagliflozin (1 mg/kg/day) for the final 3-wk. AT-001 treatment improved diastolic function in vivo (a decrease in the E/e’ ratio and an increase in the E’/A’) and reduced left ventricular mass (LV) mass in DbCM mice compared to vehicle-treated DbCM mice. Cardioprotection by AT-001 was associated with reduced cardiac AR activity, decreased circulating blood sorbitol levels, and a reduction in cardiac fatty acid oxidation rates in the DbCM mice. Treatment with dapagliflozin did not significantly affect either diastolic function or LV mass in DbCM mice. In addition, dapagliflozin did not have a significant effect on cardiac fatty acid oxidation rates.
In summary, the present study demonstrates that AT-001 attenuates diastolic dysfunction and cardiac hypertrophy in DbCM. AT-001-induced cardioprotection is accompanied by reduced cardiac fatty oxidation rates in DbCM.
Q. G. Karwi: None. R. Ramasamy: Consultant; Applied Therapeutics. J. R. Ussher: None. G. Lopaschuk: None. K. Gopal: None. S. Tabatabaei dakhili: None. C. S. Wagg: None. L. Zhang: None. Q. Sun: None. C. T. Saed: None. S. Panidarapu: None. R. Perfetti: Employee; Applied Therapeutics.