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Yagna P. Jarajapu, Ashay D. Bhatwadekar, Elena Nikonova, David L. Kent, Medina Reinhold, Alan W. Stitt, Catherine Thut, Michael E. Boulton, Mohan K. Raizada, Maria B. Grant; Activation of ACE2/Angiotensin-(1-7)/Mas Receptor Axis Enhances Vasoreparative Function of Diabetic Endothelial Progenitors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3576.
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The vasodegenerative phase of diabetic retinopathy (DR) and is to the reduced vascular repair. CD34+ endothelial progenitor cells (EPC)are dysfunctional in diabetes and have been implicated in the pathogenesis of DR. We tested if activation of the protective arm of renin angiotensin system (RAS), ACE2/Angiotensin (Ang)-(1-7)/Mas receptor axis could correct vasoreparative dysfunction in EPCs from individuals with DR. Ang-1-7, generated from Ang-II by ACE2, activates the Mas receptor.
Two study populations were examined. Study 1: Diabetic patients (n=5), free of DR despite having >40 years of poor glycemic control (deemed protected from DR) were compared to diabetics matched for age, gender, duration and glycemic control with DR (n=5). Study 2: Diabetics (n=44) with 12±2 years duration of DM and controls (n=31) were compared. Circulating Lin-CD45dimCD34+ cells were isolated from all subjects and in vitro (survival, proliferation, migration, NO bioavailability and NADPH oxidase activity) and in vivo (mouse model of retinal ischemia/reperfusion injury) functional assays were performed.
Study 1: Patients protected from DR showed elevated ACE2/Mas mRNA ratio compared to diabetics with DR (P<0.05). Study 2: ACE2 expression was lower in cells from diabetics compared to controls; however, Ang-(1-7) restored migration and NO bioavailability/cGMP production in diabetic EPCs to normal. This improvement was Mas receptor-dependent and was accompanied by a decrease in NADPH oxidase activity. Survival and proliferation of CD34+ cells from diabetics were enhanced by Ang-(1-7) in Mas receptor/PI3K/Akt-dependent manner. Ang-(1-7) overexpression by lentiviral gene modification restored in vitro vasoreparative functions in diabetic cells and enhanced their homing efficiency in vivo.
Activation of ACE2/Ang-(1-7)\Mas pathway activation corrects diabetes induced CD34+ cells dysfunction and confers protection from dysfunction in diabetic CD34+ cells. Strategies to enhance the protective arm of RAS offer a promising therapeutic approach for correcting diabetic EPC dysfunction.
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