Abstract 17750: Prolyl Hydroxylase Inhibition Induces Sdf-1 and Cxcr4 Expression to Increase Cxcr4+ Cell Homing and Myocardial Repair

Objective: Stabilization of the cardiac SDF-1/CXCR4 axis attenuates ischemic cardiomyopathy. However, HIF-1α dependent SDF-1 upregulation lasts only for 48-72 hours after myocardial infarction (MI) limiting the targeting of regenerative cells. Therefore, we hypothesized that activation of the HIF-1α target genes SDF-1 and CXCR4 by stabilization of HIF-1α through inhibition of prolyl hydroxylase stimulates myocardial repair. Methods: Genetically tagged SDF1-EGFP and CXCR4-EGFP mice were subjected to optimal doses (80mg/kg i.p.) of the prolyl hydroxylase Inhibitor dimethyloxalylglycine (DMOG). To examine the time frame of SDF-1 and CXCR4 expression in vitro (HEK cells) and in vivo (BM & heart), DMOG was treated at different dosing regimens (50μM to 1000μM & 80mg/kg i.p.) and time intervals (1 to 6 hrs). FACS and immunhistochemical analyses of CXCR4+ BM, peripheral blood, and heart cells as well as infarct size measurements and hemodynamic analyses were performed with and without DMOG treatment after MI. Results: SDF1-EGFP mice treated with DMOG showed robust induction of SDF-1 in heart vessels. In vitro , SDF-1 was transiently upregulated within 60 mins to 2 hrs after DMOG treatment, followed by significant decrease after 6hrs. CXCR4 was elevated at later time points (6h). In vivo , CXCR4 expression was significantly upregualted in BM (6h). FACS analyses of transgenic CXCR4-EGFP BM and hearts revealed that CXCR4+ was frequently expressed on CD11b+ monocytes, and at lower Levels on angiogenic CD31+ , CD34+, c-kit+, and Flk1+ cells, and stem cell populations like CD133+ and Lin-/c-kit+/Sca-1+. DMOG treatment after MI revealed a robust upregulation of CXCR4+ cell populations, predominantly of angiogenic CXCR4+/CD11b+ monocytes. Subanalysis of the latter showed that DMOG treatment leads to a shift of the CD206+/CD86 ratio in favor of M2 macrophages associated CD206+ subpopulation after MI associated by attenuated infarct remodeling. Myocardial function was significantly improved after DMOG treatment (EF: 33,5 vs. 16%). Conclusion: Our data suggest that inhibition of prolyl hydroxylase may be a promising target for HIF-1a mediated SDF-1 activation to increase CXCR4+ stem cell homing and myocardial repair.