Abstract 18567: Inhibition of Prolyl Hydroxylase to Enhance Sdf-1 Expression for Augmented Cxcr4+ Cell Recruitment and Cardiac Repair
Aims: SDF-1/CXCR4 activation facilitates myocardial repair. Since SDF-1 is only upregulated for a short time after myocardial infarction (MI) targeting of regenerative CXCR4+ cells is limited. We aimed to reactivate the HIF-1α target genes SDF-1 and CXCR4 by prolyl hydroxylase inhibition (PHI) to augment CXCR4+ cell recruitment and myocardial repair.
Methods and Results: SDF-1 and CXCR4 expression was analysed under normoxia and ischemia ± PHI utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow (BM) CXCR4-EGFP was predominantly expressed in CD45+/CXCR4-EGFP+/CD11b+ leukocytes. After MI CD45+/CXCR4-EGFP+/CD11b+ leukocytes significantly increased. In the heart CD45+/CXCR4-EGFP+ cells also predominantly co-expressed CD11b+, but also angiogenic CD31+, CD34+, c-kit+, Flk1+ markers, and stem cell populations like ACC133+, and Lin-/c-kit+/Sca-1+ significantly increased after ischemia. In vitro, PHI with 500μM dimethyloxalylglycine (DMOG) upregulated SDF-1 mRNA expression after 24 h in human microvascular endothelial cells (HMEC-1) and human aortic vascular smooth muscle cells(HAVSMC). CXCR4 was elevated at 4h in HMEC-1 and almost no detectable in HAVSMC. In vivo, CXCR4 was upregulated in BM after PHI. DMOG treatment of infarcted mice revealed an upregulation of SDF-1 protein 7 days after MI in the heart, associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ leukocytes. CXCR4-EGFP/CD11b+ cells coexpressing CD31, c-kit, Sca-1, CD68, Flk-1, CD206, CD34, and F4/80 macrophage markers were highly elevated 7 days after PHI. There was a shift of CD206/CD86 markers in favor of reparative CD206+ cells attributed to reduced scar size (12.5 ± 2.5% vs. 19.8 ± 2.4%,p<0.05) and improved ejection fraction (34.3 ± 3.7% vs. 16.9 ± 2.0%, p<0.01) after PHI.
Conclusions: Our data suggest PHI as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to augment CXCR4+ cell recruitment and cardiac repair.
Author Disclosures: S. Ghadge: None. M. Messner: None. T. Pham: None. M. Doppelhammer: None. A. Petry: None. A. Goerlach: None. B. Husse: None. W. Franz: None. M. Zaruba: None.
- © 2016 by American Heart Association, Inc.