TY - JOUR
T1 - Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+/CD11b+ subpopulations and cardiac repair
AU - Ghadge, Santhosh Kumar
AU - Messner, Moritz
AU - Van Pham, Thi
AU - Doppelhammer, Maximilian
AU - Petry, Andreas
AU - Görlach, Agnes
AU - Husse, Britta
AU - Franz, Wolfgang Michael
AU - Zaruba, Marc Michael
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Abstract: SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α 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 μM 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-1α 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. Key messages: DMOG-induced prolyl-hydroxylase inhibition upregulates SDF-1 and CXCR4 in human endothelial cells.Systemic application of DMOG upregulates nuclear HIF-1α and SDF-1 in vivo.Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells.DMOG increased reparative M2-like CD11b+/CD206+ cells compared to M1-like cells after MI.Enhanced prolyl-hydroxylase inhibition improved cardiac repair and heart function.
AB - Abstract: SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α 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 μM 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-1α 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. Key messages: DMOG-induced prolyl-hydroxylase inhibition upregulates SDF-1 and CXCR4 in human endothelial cells.Systemic application of DMOG upregulates nuclear HIF-1α and SDF-1 in vivo.Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells.DMOG increased reparative M2-like CD11b+/CD206+ cells compared to M1-like cells after MI.Enhanced prolyl-hydroxylase inhibition improved cardiac repair and heart function.
KW - CD11b
KW - CXCR4
KW - HIF-1α
KW - Myocardial ischemia
KW - Prolyl-hydroxylases inhibitors
KW - SDF-1
UR - http://www.scopus.com/inward/record.url?scp=85019748993&partnerID=8YFLogxK
U2 - 10.1007/s00109-017-1543-3
DO - 10.1007/s00109-017-1543-3
M3 - Article
C2 - 28550361
AN - SCOPUS:85019748993
SN - 0946-2716
VL - 95
SP - 825
EP - 837
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 8
ER -