Oral administration of an angiotensin-converting enzyme 2 activator ameliorates diabetes-induced cardiac dysfunction

We evaluated the hypothesis that activation of endogenous angiotensin-converting enzyme (ACE) 2 would improve cardiac dysfunction induced by diabetes. Ten days after diabetes induction (streptozotocin, 50mg/kg, i.v.), male Wistar rats were treated with the ACE2 activator 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl)sulfonyl]oxy]-9H-xanthen-9-one (XNT, 1mg/kg/day, gavage) or saline (control) for 30days. Echocardiography was performed to analyze the cardiac function and kinetic fluorogenic assays were used to determine cardiac ACE and ACE2 activities. Cardiac ACE2, ACE, Mas receptor, AT1 receptor, AT2 receptor and collagen types I and III mRNA and ACE2, ACE, Mas, AT1 receptor, AT2 receptor, ERK1/2, Akt, AMPK-α and AMPK-β1 protein were measured by qRT-PCR and western blotting techniques, respectively. Histological sections of hearts were analyzed to evaluate the presence of hypertrophy and fibrosis. Diabetic animals presented hyperglycemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. XNT treatment prevented further increase in glycemia and improved the cardiac function, as well as the hypertrophy and fibrosis. These effects were associated with increases in cardiac ACE2/ACE ratios (activity: ~26%; mRNA: ~113%; and protein: ~188%) and with a decrease in AT1 receptor expression. Additionally, XNT inhibited ERK1/2 phosphorylation and prevented changes in AMPK-α and AMPK-β1 expressions. XNT treatment did not induce any significant change in AT2 receptor and Akt expression. These results indicate that activation of intrinsic cardiac ACE2 by oral XNT treatment protects the heart against diabetes-induced dysfunction through mechanisms involving ACE, ACE2, ERK1/2, AMPK-α and AMPK-β1 modulations. ► We tested if XNT, an ACE2 activator, would improve diabetes-induced heart dysfunction. ► Diabetic rats showed heart dysfunction/hypertrophy/fibrosis which were blunted by XNT. ► ACE2 activation also increased cardiac ACE2/ACE ratio and decreased AT1 expression. ► Inhibition of ERK and modulation of AMPK-α and β1 are also involved in these effects. ► Activation of intrinsic ACE2 protects the heart against diabetes-induced dysfunction.