Activation of the ACE2/angiotensin-(1-7)/mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors

Yagna P.R. Jarajapu, Ashay D. Bhatwadekar, Sergio Caballero, Sugata Hazra, Vinayak Shenoy, Reinhold Medina, David Kent, Alan W. Stitt, Catherine Thut, Eva M. Finney, Mohan K. Raizada, Maria B. Grant

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

We tested the hypothesis that activation of the protective arm of the renin angiotensin system, the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1- 7) [Ang-(1-7)]/Mas receptor axis, corrects the vasoreparative dysfunction typically seen in the CD34+ cells isolated from diabetic individuals. Peripheral blood CD34+ cells from patients with diabetes were compared with those of nondiabetic controls. Ang-(1-7) restored impaired migration and nitric oxide bioavailability/cGMP in response to stromal cell-derived factor and resulted in a decrease in NADPH oxidase activity. The survival and proliferation of CD34+ cells from diabetic individuals were enhanced by Ang-(1-7) in a Mas/ phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. ACE2 expression was lower, and ACE2 activators xanthenone and diminazine aceturate were less effective in inducing the migration in cells from patients with diabetes compared with controls. Ang-(1-7) overexpression by lentiviral gene modification restored both the in vitro vasoreparative functions of diabetic cells and the in vivo homing efficiency to areas of ischemia. A cohort of patients who remained free of microvascular complications despite having a history of longstanding inadequate glycemic control had higher expression of ACE2/Mas mRNA than patients with diabetes with microvascular complications matched for age, sex, and glycemic control. Thus, ACE2/Ang-(1-7)\Mas pathway activation corrects existing diabetes-induced CD34+ cell dysfunction and also confers protection from development of this dysfunction.

Original languageEnglish (US)
Pages (from-to)1258-1269
Number of pages12
JournalDiabetes
Volume62
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Jarajapu, Y. P. R., Bhatwadekar, A. D., Caballero, S., Hazra, S., Shenoy, V., Medina, R., Kent, D., Stitt, A. W., Thut, C., Finney, E. M., Raizada, M. K., & Grant, M. B. (2013). Activation of the ACE2/angiotensin-(1-7)/mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors. Diabetes, 62(4), 1258-1269. https://doi.org/10.2337/db12-0808