Abstract 16652: Inhibition of Prolyl Hydroxylase as a Novel Therapeutic Target for Hif-Mediated Sdf-1 Activation and Stem Cell Homing in the Ischemic Heart
Objective: Recently published data from our lab indicate that stabilization of the cardiac SDF-1/CXCR4 axis preserves myocardial function and attenuates ischemic cardiomyopathy. After acute myocardial infarction the critical homing factor SDF-1 is only upregulated for 48-72 hours in a HIF-1α dependent manner 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 increase CXCR4+ stem cell migration.
Methods: To evaluate the effects on HIF-1α mediated SDF-1 expression, genetically tagged SDF1-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 marrow, peripheral blood, and heart cells were analyzed under normoxaemic and ischemic conditions with and without DMOG.
Results: SDF1-EGFP reporter mice treated with DMOG showed robust induction of SDF-1 in the heart. FACS of transgenic CXCR4-EGFP 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 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 of the latter showed expression of Sca1+, CD86+, CD206+ and F4/80+. DMOG treatment leads especially to upregulation of the CD206+ subpopulation in the infarcted hearts in favor of repair mechanisms. In conclusion , our data suggest that CXCR4 is highly expressed on angiogenic and stem cells in the ischemic myocardium. Proly hydroxylase inhibitors may be a novel promising therapeutic target for HIF-1α mediated SDF-1 activation to increase stem cell homing and myocardial repair.
- © 2013 by American Heart Association, Inc.