Abstract 18569: Inhibition of Prolyl Hydroxylase Stimulates Hif-mediated Sdf-1 Expression and CXCR4+ Cell Recruitment for Myocardial Repair

Abstract

Objective: Data from our lab indicate that stabilization of the cardiac SDF-1/CXCR4 axis preserves myocardial function and attenuates ischemic cardiomyopathy. However, HIF-1α dependent SDF-1 upregulation lasts only for 48-72 hours after MI limiting the targeting of stem cells to ischemic myocardium. To overcome this caveat, we aimed to activate SDF-1 expression by stabilization of HIF-1α through inhibition of prolyl hydroxylase with the ratio to augment CXCR4+ stem cell recruitment and stimulate myocardial repair. Methods: To evaluate the effects on HIF-1α mediated SDF-1 expression, genetically taggedSDF1-EGFP mice were subjected to optimal doses (80mg/kg i.p.) of the prolyl hydroxylase Inhibitor dimethyloxalylglycine (DMOG). To track the fate of CXCR4+ cells, genetically tagged CXCR4-EGFP BAC reporter mice were utilized. FACS and immunhistochemical analyses of CXCR4+ bone marrowm(BM), peripheral blood, and heart cells as well as infarct sizes were analyzed under normoxaemic and ischemic conditions with and without DMOG treatment. Results: SDF1-EGFP mice treated with DMOG showed robust induction of SDF-1 in the heart. SDF-1 upregulation after DMOG treatment was further confirmed by SDF-1 ELISA of heart lysates. FACS of transgenic CXCR4-EGFP BM and hearts revealed that CXCR4+ was most frequently expressed on CD11b+ monocytes, and to a less amount on angiogenic CD31+ , CD34+, c-kit+, and Flk1+ cells, as well as stem cell populations like ACC133+ and Lin-/c-kit+/Sca-1+. After myocardial ischemia these cell populations were highly upregulated. A subpopulation of CXCR4-EGFP+ cells co-expressed CD31 in capillaries. Treatment with DMOG revealed a robust upregulation of CXCR4+ cell populations in the ischemic heart, predominantly of angiogenic CXCR4+/CD11b+ monocytes. Further analysis showed that DMOG Treatment after 7 days leads particularly to upregulation of CD206+ subpopulation in infarcted hearts in favor of repair mechanisms characterized by reduced infarct sizes. Summary and Conclusion: Our data suggest that inhibition of prolyl hydroxylase may be a promising target for HIF-1a mediated SDF-1 activation to increase stem cell homing and myocardial repair.