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.
Author Disclosures: S. Ghadge: None. T. Pham: None. M. Messner: None. M. Doppelhammer: None. B. Husse: None. W. Franz: None. M. Zaruba: None.
- © 2015 by American Heart Association, Inc.