Abstract
Evidence from clinical trials suggests that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may arise through non-glycemic control-related mechanisms. Further, the cardiovascular advantages of SGLT2 inhibitors are likely present among non-diabetic patients with known cardiovascular diseases (CVDs). Here, we studied the impact of ipragliflozin, a selective SGLT2 inhibitor, on cardiac histopathology and microRNA (miRNA) expression profiles in a non-diabetic rat model of cardiomyopathy. Ipragliflozin was added to chow (0.01% (w/w)) and given to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 6 weeks. Similarly aged male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats were treated as controls. Measurements of systolic blood pressure (SBP) and heart rate (HR) were taken every other week. Following ipragliflozin treatment for 6 weeks, we conducted echocardiography, histopathological examination, and miRNA expression analysis (microarray). The impact of ipragliflozin on blood parameters was additionally examined. In DS/obese rats, ipragliflozin reduced SBP without affecting HR, reduced interventricular septal thickness in echocardiography and left ventricular (LV) organ weight, and improved hypertrophy of cardiomyocytes according to histopathological experiments. Further, ipragliflozin reduced plasma inflammatory cytokine levels in DS/obese rats. Additionally, ipragliflozin treatment altered the expression profile of miRNAs related to cardiac hypertrophy and heart failure in the LV compared to DS/obese control rats. Ipragliflozin prevented LV hypertrophy and altered related miRNA expression profiles in non-diabetic DS/obese rats. These findings suggest that miRNAs may play a partial role in regulating the structure of the heart and that SGLT2 inhibitors may exert cardio-protective effects by changing miRNA expression profiles in non-diabetic patients with CVDs.