Abstract 557: ACE2/Angiotensin-(1-7) Stimulates Vasoprotection-Relevant Functions of Human CD34 + Cells

Abstract

Angiotensin converting enzyme 2 (ACE2) and angiotensin (Ang)-(1-7), key members of the vasoprotective axis of the renin-angiotensin system (RAS), have been shown to modulate hematopoietic functions of bone marrow-derived cells. This coupled with recent studies implicating the involvement of bone marrow stem/progenitor cells in the cardiovascular functions, we evaluated the expression of RAS components and functions of ACE2 and Ang-(1-7) in human CD34 + cells, hematopoietic stem cells with vasoprotective functions. Peripheral blood was obtained from healthy individuals and CD34 + cells were isolated by immunomagnetic separation. Real-time PCR was carried out, and the effects of Ang II, Ang-(1-7), NorLeu 3 Ang-(1-7), and ACE2 activators, diminazene aceturate (DIZI) and a xanthenone derivative (XNT), were evaluated on migration, proliferation and adhesion of CD34 + cells. Paracrine factors produced by CD34 + cells were analyzed. CD34 + cells showed the presence of mRNA transcripts of ACE, ACE2 and Mas1 receptor. In contrast, renin, angiotensinogen, and AT1 and AT2 receptors were not detectable. Treatment with 100nM Ang-(1-7) or 10nM NorLeu 3 Ang-(1-7) stimulated proliferation and migration of CD34 + cells while adhesion of these cells to fibronectin was not affected. Ang-(1-7) treatment altered the paracrine profile of CD34 + cells: increased IL10, IL8, G-CSF, GM-CSF, IGFBP-3 and decorin (P<0.03), and decreased IGF1, thrombopoietin and TGFβ1 levels (P<0.05, n=5). In contrast, 100nM Ang II has no effects on proliferation and migration of CD34 + cells. However, in the presence of Ang II, 100nM DIZI or 100nM XNT increased proliferation and migration of CD34 + cells compared to the cells treated with Ang II alone (P<0.05, n=7). Treatment of total leucocytes with Ang II prior to the isolation of CD34 + cells attenuated their migration to stromal-derived factor-1α and proliferation compared to the untreated (P<0.05, n=5), and enhanced their adhesion to fibronectin. These studies suggest that activation of endogenous ACE2 or treatment with Ang-(1-7) stimulates the functions of CD34 + cells that are indicators of their cardiovascular protective functions while Ang II may attenuate these properties indirectly via acting on leucocytes.