title: Activation of the ACE2/angiotensin-(1-7)/Mas receptor axis enhances the reparative function of dysfunctional diabetic endothelial progenitors.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
authors.forename: Yagna P R
authors.initials: YP
authors.lastname: Jarajapu
authors.forename: Ashay D
authors.initials: AD
authors.lastname: Bhatwadekar
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.forename: Sugata
authors.initials: S
authors.lastname: Hazra
authors.forename: Vinayak
authors.initials: V
authors.lastname: Shenoy
authors.forename: Reinhold
authors.initials: R
authors.lastname: Medina
authors.forename: David
authors.initials: D
authors.lastname: Kent
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
authors.forename: Catherine
authors.initials: C
authors.lastname: Thut
authors.forename: Eva M
authors.initials: EM
authors.lastname: Finney
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000328:Adult; D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)