Circulating rather than cardiac angiotensin-(1-7) stimulates cardioprotection after myocardial infarction
Background: Angiotensin (Ang)-(1-7) attenuates the development of heart failure. In addition to its local effects on cardiovascular tissue, Ang-(1-7) also stimulates bone marrow, which harbors cells that might complement the therapeutic effect of Ang-(1-7). We studied the effects of Ang-(1-7) either produced locally in the heart or subcutaneously injected during the development of heart failure induced by myocardial infarction (MI) and explored the role of cardiovascular progenitor cells in promoting the effects of this heptapeptide. Methods and Results: Effects of Ang-(1-7) on bone marrow-derived mononuclear cells in rodents, particularly endothelial progenitor cells, were investigated in vitro and in vivo in rats, in mice deficient for the putative Ang-(1-7) receptor Mas, and in mice overexpressing Ang-(1-7) exclusively in the heart. Three weeks after MI induction through permanent coronary artery occlusion, effects of Ang-(1-7) either produced locally in the heart or injected into the subcutaneous space were investigated. Ang-(1-7) stimulated proliferation of endothelial progenitor cells isolated from sham or infarcted rodents. The stimulation was blunted by A779, a Mas receptor blocker, or by Mas deficiency. Infusion of Ang-(1-7) after MI increased the number of c-kit-and vascular endothelial growth factor-positive cells in infarcted hearts, inhibited cardiac hypertrophy, and improved cardiac function 3 weeks after MI, whereas cardiomyocyte-derived Ang-(1-7) had no effect. Conclusions: Our data suggest circulating rather than cardiac Ang-(1-7) to be beneficial after MI. This beneficial effect correlates with a stimulation of cardiac progenitor cells in vitro and in vivo. This characterizes the heptapeptide as a promising new tool in stimulating cardiovascular regeneration under pathophysiological conditions.