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

Yagna P R Jarajapu, Ashay 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

45 Citations (Scopus)

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
Externally publishedYes

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Enzyme Activators
Phosphatidylinositol 3-Kinase
NADPH Oxidase
Renin-Angiotensin System
Stromal Cells
Biological Availability
Cell Movement
Blood Cells
Nitric Oxide
Ischemia
Cell Proliferation
angiotensin I (1-7)
angiotensin converting enzyme 2
Messenger RNA
Survival
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Activation of the ACE2/angiotensin-(1-7)/mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors. / Jarajapu, Yagna P R; Bhatwadekar, Ashay; Caballero, Sergio; Hazra, Sugata; Shenoy, Vinayak; Medina, Reinhold; Kent, David; Stitt, Alan W.; Thut, Catherine; Finney, Eva M.; Raizada, Mohan K.; Grant, Maria B.

In: Diabetes, Vol. 62, No. 4, 04.2013, p. 1258-1269.

Research output: Contribution to journalArticle

Jarajapu, YPR, Bhatwadekar, A, Caballero, S, Hazra, S, Shenoy, V, Medina, R, Kent, D, Stitt, AW, Thut, C, Finney, EM, Raizada, MK & Grant, MB 2013, 'Activation of the ACE2/angiotensin-(1-7)/mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors', Diabetes, vol. 62, no. 4, pp. 1258-1269. https://doi.org/10.2337/db12-0808
Jarajapu, Yagna P R ; Bhatwadekar, Ashay ; Caballero, Sergio ; Hazra, Sugata ; Shenoy, Vinayak ; Medina, Reinhold ; Kent, David ; Stitt, Alan W. ; Thut, Catherine ; Finney, Eva M. ; Raizada, Mohan K. ; Grant, Maria B. / Activation of the ACE2/angiotensin-(1-7)/mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors. In: Diabetes. 2013 ; Vol. 62, No. 4. pp. 1258-1269.
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