title: ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells.
abstract: CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings imply that activation of ACE2/Ang-(1-7)/Mas axis is a promising approach for enhancing reparative outcomes of cell-based therapies.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota;
authors.forename: Neha
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota;
authors.forename: Shrinidh
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota; Department of Pathophysiology, College of Basic Medical Science, Jilin University, Changchun, Jilin, China;
authors.forename: Lirong
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, Florida; and.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Baker
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, Florida; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, Florida; and.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Castellano
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota; Yagna.Jarajapu@ndsu.edu.
authors.forename: Yagna P R
authors.initials: YP
authors.lastname: Jarajapu
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D018952:Antigens, CD34; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology
chemical_list: C544065:AGTR1 protein, human; D018952:Antigens, CD34; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D044004:Xanthones; C473306:norLeu3-A(1-7); D000804:Angiotensin II; D000803:Angiotensin I; C009689:xanthone; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); C003915:diminazene aceturate; D004133:Diminazene
keywords: ACE-2; Ang-(1–7); CD34+ cells; Mas receptor; migration; proliferation