Abstract 72: Potentiation of Reparative Capacity of Cardiac Progenitor Cells (cpcs, Islet-1+) by Angiotensin-(1-7) in Myocardial Infarction (MI)-induced Cardiac Damage
Background: Endogenous myocardial regeneration is insufficient to fully rescue hemodynamic functions following MI. Stem cell therapy has been attempted to provide exogenous reparative support to ameliorate cardiac regeneration with limited success. We evaluated the hypothesis that transduction of CPCs with Ang-(1-7) would improve their reparative capacity, since this vasoprotective axis of the renin angiotensin system is implicated in progenitor cell functions.
Methods: CPCs were isolated from adult rats, characterized by the presence of Islet-1 in the nuclei and expression of GATA4 and Nkx2-5. Their transduction with Lenti-Ang-(1-7) resulted in a 20-fold increase in Ang-(1-7) production. 4 × 106 of CPCs, or lenti-Ang-(1-7) transduced CPCs, were injected via the jugular vein three days after permanent left anterior descending coronary artery ligation. Echocardiography, hemodynamic, histological parameters, and capillary vessel density were measured to assess cardiac function and effects of cell transplantation four weeks thereafter.
Results: First we determined if Ang-(1-7) improves CPC functions in vitro. Hypoxia inhibited the migration of CPCs, whereas Ang-(1-7) protected CPCs from hypoxia induced inhibition of migration. Results from the in vivo studies demonstrated that MI significantly reduced fractional shortening (FS, 33.0% ± 1.5 vs 59.5% ± 1.9 for control), increased ventricular hypertrophy (VH, 3.6 ± 0.1 vs 2.7 ± 0.1 for control, (g/kg)), and decreased dP/dtmax (7235 ± 271.9 vs 10394 ± 326.3 for control, mmHg/sec). In comparison to MI, CPCs alone restored FS by 22%, reversed VH by 11%, and improved dP/dtmax by 23%. Remarkably, Ang-(1-7) expressing CPCs further improved FS by 44%, decreased VH by 15%, and attenuated the reduction in dP/dtmax by 42%. Finally, capillary density in the peri-infarct myocardium was increased by 59% with CPCs alone and this capillary density was further increased by 139% with Ang-(1-7) expressing CPCs.
Conclusions: These observations, for the first time, demonstrate that Ang-(1-7) enhances CPC capacities to improve cardiac hemodynamic and circulation following MI. They suggest that Ang-(1-7) transduced CPC could be an improved stem cell therapy strategy for the treatment of ischemic heart disease.
- © 2012 by American Heart Association, Inc.