Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+subpopulations and cardiac repair

Ghadge, Santhosh Kumar; Messner, Moritz; Pham, Thi Van; Doppelhammer, Maximilian; Petry, Andreas; Görlach, Agnes; Husse, Britta; Franz, Wolfgang-Michael und Zaruba, Marc-Michael (2017): Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+subpopulations and cardiac repair. In: Journal of Molecular Medicine-Jmm, Bd. 95, Nr. 8: S. 825-837

Abstract

SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1 alpha target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia +/- DMOG utilizing SDF-1-EGFP and CXCR4-EGFP reporter mice. In bone marrow and heart, CXCR4-EGFP was predominantly expressed in CD45+/CD11b+ leukocytes which significantly increased after myocardial ischemia. PH inhibition with 500 mu M DMOG induced upregulation of SDF-1 mRNA in human microvascular endothelial cells (HMEC-1) and aortic vascular smooth muscle cells (HAVSMC). CXCR4 was highly elevated in HMEC-1 but almost no detectable in HAVSMC. In vivo, systemic administration of the PH inhibitor DMOG without pretreatment upregulated nuclear HIF-1 alpha and SDF-1 in the ischemic mouse heart associated with increased recruitment of CD45+/CXCR4-EGFP+/CD11b+ cell subsets. Enhanced PH inhibition significantly upregulated reparative M2 like CXCR4-EGFP+CD11b+/CD206+ cells compared to inflammatory M2-like CXCR4-EGFP+CD11b+/CD86+ cells associated with reduced apoptotic cell death, increased neovascularization, reduced scar size, and an improved heart function after MI. In summary, our data suggest increased PH inhibition as a promising tool for a customized upregulation of SDF-1 and CXCR4 expression to attract CXCR4+/CD11b+ cells to the ischemic heart associated with increased cardiac repair.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0946-2716
• Sprache: Englisch