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.

Reversal of Bone Marrow Mobilopathy and Enhanced Vascular Repair by Angiotensin-(1-7) in Diabetes

“…4 C ). In agreement with this and our previous studies in human CD34 + cells (19), SDF- or VEGF-induced migration of LSK cells in vitro was attenuated by Y-27632, a ROCK inhibitor ( P < 0.05, vs. SDF) (Fig. 4 E ).…”

Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells

“…Recent studies showed that local RAS modulate hematopoietic and cardiovascular reparative functions of BMSPCs (Rodgers and diZerega, 2013). We and others have shown evidence for the expression of mRNA and protein of ACE or ACE2 in human and mouse BMSPCs (Abali et al, 2002; Oliveira et al, 2010; Thatcher et al, 2011; Jarajapu et al, 2013; Singh et al, 2015). …”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…XNT adminstration also prevented the increase in right ventricular systolic pressure and hypertrophy in a monocrotaline-induced pulmonary hypertension model (169) and attenuated thrombus formation in SHR (190). Numerous protective effects have been reported with diminazene aceturate (DIZE), another putative ACE2 activator (102,118,119,184,186,335,341,357,429,445,511,513,535,566). It should be pointed out, however, that the beneficial effects of these small-molecule activators might also depend on ACE2-independent mechanisms (234).…”