Overexpression of Angiopoietin-1 Increases CD133+/c-kit+ Cells and Reduces Myocardial Apoptosis in db/db Mouse Infarcted Hearts

Abstract

Hematopoietic progenitor CD133⁺/c-kit⁺ cells have been shown to be involved in myocardial healing following myocardial infarction (MI). Previously we demonstrated that angiopoietin-1(Ang-1) is beneficial in the repair of diabetic infarcted hearts. We now investigate whether Ang-1 affects CD133⁺/c-kit⁺ cell recruitment to the infarcted myocardium thereby mediating cardiac repair in type II (db/db) diabetic mice. db/db mice were administered either adenovirus Ang-1 (Ad-Ang-1) or Ad-β-gal systemically immediately after ligation of the left anterior descending coronary artery (LAD). Overexpression of Ang-1 resulted in a significant increase in CXCR-4/SDF-1α expression and promoted CD133⁺/c-kit⁺, CD133⁺/CXCR-4⁺ and CD133⁺/SDF-1α⁺ cell recruitment into ischemic hearts. Overexpression of Ang-1 led to significant increases in number of CD31⁺ and smooth muscle-like cells and VEGF expression in bone marrow (BM). This was accompanied by significant decreases in cardiac apoptosis and fibrosis and an increase in myocardial capillary density. Ang-1 also upregulated Jagged-1, Notch3 and apelin expression followed by increases in arteriole formation in the infarcted myocardium. Furthermore, overexpression of Ang-1 resulted in a significant improvement of cardiac functional recovery after 14 days of ischemia. Our data strongly suggest that Ang-1 attenuates cardiac apoptosis and promotes cardiac repair by a mechanism involving in promoting CD133⁺/c-kit⁺ cells and angiogenesis in diabetic db/db mouse infarcted hearts.