Abstract 197: Effects of a Stabile Angiotensin-(1-7) Analogue, Cyclic Angiotensin-(1-7), on Progenitor Cell Recruitment and Cardiac Remodeling

Abstract

Objectives: In animal models, angiotensin-(1-7) treatment has beneficial effects improving cardiac function and remodeling after myocardial infarction (MI). Angiotensin-(1-7) might have a beneficial angiogenic effect after MI, since infusion increases the number of progenitor and VEGF+ cells in the heart. Angiotensin-(1-7) also promotes the in vitro differentiation of endothelial progenitor cells (EPC), and tube formation. For optimal clinical use, metabolically stable 4-Ser,7-Cys-thioether-bridged angiotensin-(1-7), called cyclic angiotensin-(1-7) (cAng-(1-7)), has been developed. We studied the effect of cAng-(1-7) treatment on progenitor cells recruitment and early cardiac remodeling after MI, with an emphasis on angiogenic properties. Design and Methods: Angiogenic progenitor cell recruitment was measured 24 h after a bolus injection of 50 ug/kg cAng-(1-7) in healthy mice by flow cytometric counting of ckit+, sca-1+ and flk1+ cells in blood and bone marrow. In addition, mice underwent coronary ligation or sham surgery and either saline or 2.4 ug/kg/h cAng-(1-7). After 3 weeks of treatment, cardiac function was measured by intraluminal pressure catheter. Cardiac vascular density, fibrosis and myocyte dimensions were assessed. Furthermore, we studied the dose-related effects of normal and cAng-(1-7) on tube formation by HUVEC. Results: cAng-(1-7) increased blood ckit+, sca-1+ and flk1+ cells, which tended to decrease in bone marrow. cAng-(1-7) reduced cardiomyocyte hypertrophy (476±99μm 2 vs 292±78μm 2 /cell) compared to saline, but showed no effect on heart weight, infarct size, fibrosis and vascular density. Cardiac contractile function was not improved by cAng-(1-7). Tube formation by HUVEC was reduced by cAng-(1-7) as well as by native Ang-(1-7). Conclusions: Our results suggest that cAng-(1-7) given early after MI might not lead to improved angiogenesis, despite an increased recruitment of hematopoietic and endothelial-like cells from the bone marrow. This might explain why there is no swift beneficial effect of cAng-(1-7) on cardiac performance despite a reduction of myocyte hypertrophy. Further optimization of cAng-(1-7) treatment and evaluation of treatment lasting longer than 3 weeks will be necessary.