Pioglitazone Alters Ace/Ace 2 Balance to Favour Ace2 Independently Of Glycaemia Levels in Diabetic Rat Heart

The activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiac damage during diabetes. In the present study, we investigated the role of pioglitazone, dapagliflozin and their combination on RAS components in streptozotocin-induced diabetic cardiomyopathy in Wistar rats. Blood glucose, serum lipids, and ACE (angiotensin-converting enzyme), ACE2 levels were determined. mRNA levels of Myh6 (myosins heavy chain), Myh7, Ace, Ace2, Nppa, Nppb (natriuretic peptide A, B) and Ppars (peroxisome proliferator activating receptors) genes in the heart were determined by real-time PCR (polymerase chain reaction). Protein expression of ACE and ACE2 was assessed by western blotting. After six weeks pioglitazone suppressed Ace mRNA and protein levels (p<0.05) and modified the Ace/Ace2 ratio (p<0.05) in the cardiac tissue of diabetic rats. Pioglitazone significantly decreased serum lipids (p<0.05) but did not significantly influence blood glucose and ACE serum levels of diabetic animals. Dapagliflozin had a significant glucose-lowering action (p<0.05) however, it had no impact on the Ace/Ace2 ratio. The combination of both compounds markedly improved blood glucose (p<0.05) as well as the Myh6/Myh7 ratio (p<0.05) but had no further impact on the Ace to Ace2 balance in cardiac tissue compared to pioglitazone monotherapy. We found that pioglitazone improves the cardiac Ace/ Ace2 ratio in diabetic rats suggesting a potential cardioprotective effect. This effect is independent of its antidiabetic and metabolic effects.