Cardiovascular diseases, including diabetic cardiomyopathy (DbCM), are major causes of death in people with type 2 diabetes (T2D). Several studies have suggested that aldose reductase (AR), an enzyme activated under hyperglycemic conditions, can alter cardiac energy metabolism and deteriorate cardiac function. We investigated whether inhibition of AR, using a next-generation inhibitor AT-001, can mitigate DbCM by modulating cardiac energy metabolism. Human AR overexpressing transgenic (hAR-Tg) and control C57BL/6J mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wks with a single intraperitoneal streptozotocin injection of 75 mg/kg at 4-wks). AR inhibition by AT-001 treatment (40 mg/kg/daily) for 3-wks significantly improved cardiac energetics in hAR-Tg mice with T2D. AT-001 treated mice exhibited significantly decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (608 ± 66 vs. 1200 ± 176 nmol.min-1.g dry wt-1, respectively), which was accompanied by a decrease in cardiac oxygen consumption in AT-001 treated mice (44 ± 8 vs. 61 ± 11 µmol.min-1.g dry wt-1). Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DbCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio (1.6 ± 0.12 vs. 1.38 ± 0.1) and decrease in E/E’ ratio (26.6 ± 1 vs. 33 ± 4.9). AT-001 treatment also prevented cardiac hypertrophy as reflected by a decrease in LV mass (90.5 ± 2.2 vs. 125 ± 14 mg). We conclude that AT-001 prevents cardiac structural and functional abnormalities in DbCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a nondiabetic metabolic state.
K. Gopal: None. Q. G. Karwi: None. S. Tabatabaei dakhili: None. C. S. Wagg: None. R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. R. Ramasamy: Consultant; Self; Applied Therapeutics, Research Support; Self; Applied Therapeutics. J. R. Ussher: None. G. Lopaschuk: None.