Abstract 13757: An ACE2 Activator (DIZE) Improves Endothelial Progenitor Cell Function in Patients with Pulmonary Hypertension
Purpose: Recent evidence indicates that dysfunctional bone marrow (BM) derived endothelial progenitor cells (EPC) are associated with pulmonary hypertension (PH). Correction of this dysfunction could attenuate PH. Previously, we have shown that angiotensin converting enzyme2 (ACE2) overexpression prevents PH. Together, these observations have led us to hypothesize that ACE2 activation would rescue EPC dysfunction in patients with PH and in animal models of this disease. We tested this hypothesis by using Diminazene aceturate (DIZE), an ACE2 activator.
Methods: Peripheral blood mononuclear cells (MNC) from control (n=20) and PH patients (n=25) were enriched for CD34+EPC and evaluated for their migratory function. For animal studies, PH was induced by a single 50mg/Kg s.c injection of monocrotaline (MCT). A subset of MCT rats was treated with DIZE (15mg/Kg/day s.c) for 28 days. BM derived mononuclear cells were enriched for CD90+ cells, an EPC marker in rats, to assess proliferation and migratory capacity.
Results: Circulating EPC from PH patients were decreased by 62% compared with age-sex matched control (Control: 0.44±0.1%; PH: 0.17±0.04% of total MNC; p<0.008). Furthermore, the migratory capacity of PH-EPC to the key stimulatory cytokine SDF was reduced by 73% (p<0.01). However, when these cells were co-incubated with Ang-(1-7), migration was enhanced by 118% (p<0.05). Pretreatment of PH-EPC with DIZE also increased SDF-induced migration (81±6% vs untreated 27±5%; p<0.01). MCT-rats had elevated RVSP (Control: 31 + 3; MCT: 57+7mmHg; p<0.05) and RVH (Control: 0.23+0.004; MCT: 0.43+0.03; p<0.05), which was prevented by DIZE (MCT+ DIZE: RVSP: 41+ 4mmHg and RVH: 0.26+0.01; p<0.05). Decreased relaxation to acetylcholine was observed in preconstricted pulmonary arteries of MCT-rats (Control: 80%; MCT: 29%; p<0.05), which was improved by DIZE (MCT+DIZE: 50%; p<0.05). CD90+ cells from MCT-rats showed two-fold decrease in migration and proliferation towards SDF which was prevented by DIZE treatment.
Conclusions: Our findings show that PH is associated with decreased numbers and dysfunctional EPC. Treatment with DIZE rescues EPC function and prevents PH. Our results suggest that ACE2 may be critical for EPC function and their ability to attenuate PH.
- © 2011 by American Heart Association, Inc.