Abstract 18970: Angiotensin-(1-7) Enhances the Regenerative Capacity of Cardiac Progenitor Cells (CPCs, Islet-1 + ) in Ischemia-induced Cardiac Injury Model

Abstract

Stem cell therapy has achieved limited success to provide sufficient exogenous reparative support in ischemic heart diseases (IHD). We evaluated the hypothesis that transduction of CPCs with Ang-(1-7) would improve their regenerative capacity, as this peptide has been shown to improve hematopoietic progenitor cell functions. First, we determined if Ang-(1-7) improves CPC functions in vitro . Angiogenesis and migratory potential of CPCs, lenti-Ang-(1-7) transduced CPCs and CPCs treated with 1µM Ang-(1-7) were evaluated. Ang-(1-7) enhanced the CPC capability to form tubes; protected CPCs from hypoxia (H) induced inhibition of migration (CPC 688.7 ± 52.8, H treated CPC 124.5 ± 187.7, H+lenti-Ang-(1-7) 617.2 ± 45.4, H+1µM Ang-(1-7) 878.8 ± 303.9; RFU); reduced ACE mRNA level in the CPCs and shifted the balance to the vasoprotective axis of the RAS. Next, in vivo studies were carried out by injecting CPCs or lenti-Ang-(1-7) transduced CPCs (4 × 10 6 ), into 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 the effects of cell transplantation four weeks thereafter. Results from the in vivo studies demonstrated that myocardial infarction (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 ± 0.1for control, (g/kg)), and decreased dP/dt max (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/dt max by 23%. Remarkably, Ang-(1-7) expressing CPCs further improved FS by 44%, decreased VH by 15%, and attenuated the reduction in dP/dt max 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. In conclusion, these observations, for the first time, demonstrate that Ang-(1-7) enhances the regenerative capacity of CPCs and promotes angiogenesis to improve cardiac hemodynamic following MI. They suggest that Ang-(1-7) transduced CPC could have therapeutic potential in IHD.