Abstract 905: Hypoxia Inducible Factor 1α-Mediated Paracrine Signaling from the Myocardium Regulates Recruitment of Bone Marrow-Derived Cells.
Background: Bone marrow-derived cells (BMDC) play an essential role in the cardiac response to injury, as inflammatory cells and as progenitor cells. Understanding the mechanisms whereby these cells are recruited to the heart may define new targets for therapeutic intervention. Hypoxia, is present in many types of cardiac injury, and may serve as a signal for the recruitment of BMDC. To investigate this we focused on the HIF (hypoxia-inducible factor) pathway.
Methods and Results: In a series of in vitro experiments we show that HIF-1α expressed in cardiac myocytes mediates secretion of a paracrine factors that incease chemotaxis of BMDC by 53 % compared to control. The use of an anti VEGF antibody reduces this increase by (67 %; P< 0.01). Further, we show that this paracrine function mediates significant increases in PECAM and E-selectin on endothelial cells, and increases adhesion of BMDC to these cells. In a murine infarct model in vivo we demonstrate a 67 % increase in the recruitment of Sca1+/lin- cells to hearts transduced with Ad-HIF1 α vs. control virus (P=0.04). Using a Cre-lox approach to delete HIF1α from cardiac myocytes, in conjunction with an isolated-perfused heart system, we show that loss of HIF in the heart reduces BMDC retention in the post-ischemic heart by 23% (P=0.01). We further show that cardiomyocyte HIF null hearts express less PECAM-1 and less E-selectin, suggesting a mechanism whereby loss of HIF leads to decreased paracrine induction of adhesion complexes and thus decreased BMDC retention. Finally, using wild-type hearts we demonstrate that antibodies to either PECAM or E-selectin can decrease BMDC recruitment to the heart, by 63 % and by 34 % (P=0.02 and P=0.02, respectively)
Conclusion: This data establishes a crucial role for the HIF pathway in mediating BMDC recruitment to the heart, and underscores the role of the myocardial-endothelial crosstalk in this.