The Angiotensin-Converting Enzyme 2/Angiotensin-(1-7)/Mas Receptor Axis: A Potential Target for Treating Diabetic Cardiovascular Disease

Activation of the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type-1 receptor (AT1) axis in the heart and vasculature plays an important role in the development of diabetic complications. The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis has been shown to oppose the actions of Ang II. Our results have shown that chronic treatment with Ang-(1-7) led to correction of the altered responses to norepinephrine or endothelin-1 and carbachol in the mesenteric bed, carotid, and renal arteries of diabetic rats and improved recovery of left ventricular function from 40 min of global ischemia. We showed that the beneficial effects of Ang-(1-7) on the diabetic vasculature involve inhibition of the detrimental EGFR/ERK1/2/p38MAP kinase pathway. Ang-(1-7) treatment inhibited cardiac NADPH oxidase (NOX) and cardiac nuclear factor-κB (NF-κB) activity and also suppressed the expression of several pro-inflammatory genes involved in the NF-κB signaling pathway, including complement component 3 (C3), interleukin 1-beta (Il-1β), interleukin 6 (Il-6), NACHT-containing protein (Nalp12), and caspase 1 (Casp1). We conclude that activation of the Ang-(1-7)-mediated signal transduction pathway appears to be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.