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

Abstract

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 30 days. 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 type 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 expression. 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 modulation.

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Myocardial Injury via Activation of the CTGF-Fractalkine Signaling Pathway

“…Consistent with exacerbation of AngII pathological hypertrophy and ultrastructural injury, AngII-induced cardiac dysfunction was greater in ACE2KO mice than activation of endogenous ACE2 by treatment with the ACE2 agonist, XNT, or rhACE2 has been shown to improve cardiac hypertrophy and dysfunction with downregulation of MAPK/ ERK signaling and upregulation of the ACE2/ACE ratio. 3, 18 In this work, we demonstrated that in AngII-induced hypertensive mice with myocardial hypertrophy and ultrastructure deterioration, the levels of CTGF and FKN were upregulated in the heart, with marked increases in phosphorylated ERK1/2 and expression of MCP-1. Our data confirm the activation of the myocardial CTGF-FKN-ERK signaling pathway in Ace2 -/y mutant mice.…”

“…2,3,15 -19 In the heart, ACE2 is expressed in cardiomyocytes, fibroblasts, and endothelial cells. 3,8,11, 18 Our previous studies have demonstrated that ACE2 overexpression prevents AngII-mediated cardiovascular inflammation and injury associated with reduced MMP2 level, 3,8,11 suggesting a critical role of ACE2 in the regulation of cardiovascular injury and dysfunction. However, the exact roles and mechanisms of ACE2 in the cardiovascular system remain largely unknown.…”

Increase of angiotensin-converting enzyme activity and peripheral sympathetic dysfunction could contribute to hypertension development in streptozotocin-induced diabetic rats

“…25 More relevant to the present study are the old 26 and recent observations 27 that the plasma ACE activity is increased in diabetic patients. In this sense, our data showed an elevation of circulating ACE activity in diabetic rats D30 and D60 (Figure 1(d)).…”

Antiglaucomatous Effects of the Activation of Intrinsic Angiotensin-Converting Enzyme 2

“…Increased ACE2 expression is a frequent finding when using ACE2 activators. 24,25 This behavior strongly suggests that these compounds induce their beneficial effects, not only by forming Ang-(1-7) and/or degrading Ang II when acting as an ACE2 activator, but also through an unidentified mechanism that is able to induce the expression of ACE2. It is important to note that the effectiveness of DIZE as an activator of ACE2 was previously demonstrated by the analysis of the cleavage of Ang II.…”