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

Abstract

Ischemic cardiomyopathy due to acute myocardial infarction (MI) or coronary artery disease is a major contributor for mortality and morbidity in the Western world with rising incidence [ 1 , 2 ]. Although pharmacological therapies can limit progression to chronic end-stage heart failure, repair of functional myocardium is very limited. Stromal cell-derived factor-1 (SDF-1) and its corresponding receptor CXCR4 have been shown to play prominent roles during cardiovascular development, cardiac repair, and tissue homeostasis after ischemia [ 3 ]. We could demonstrate that a dual therapy consisting of (stem) cell mobilization with granulocyte-colony stimulating factor (G-CSF) and stabilization of SDF-1 by preventing its cleavage through inhibition of the protease CD26 increased recruitment of blood-derived progenitor cells associated with attenuated post-MI remodeling, improved myocardial function, and increased survival in mice [ 4 ]. Combined G-CSF treatment with dipeptidyl peptidase-IV (DPP-IV) inhibition limiting the proteolytic degradation of SDF-1 plus cell cycle activation in cardiomyocytes even enhanced cardiac regeneration after MI [ 5 ]. SDF-1 is upregulated for only ca. 3 days after MI, limiting the targeting of circulating CXCR4+ progenitors to ischemic myocardium over a longer period of post-infarct remodeling [ 6 ]. Consequently, various groups have developed strategies to overexpress SDF-1 mRNA or deliver SDF-1 protein after acute myocardial infarction in the heart to attenuate ischemic cardiomyopathy [ 7 , 8 , 9 ]. As a hindrance, these strategies rely on invasive procedures with the risk for infections and bleeding. From a translational aspect, it would be desirable to customize SDF-1 and CXCR4 gene expression pharmacologically in a time-dependent manner. Hypoxia-inducible factor (HIF) prolyl-hydroxylases seem to be attractive tools to achieve this goal: SDF-1 and CXCR4 gene expression is regulated by HIF-1α, which can bind to both promoters [ 10 , 11 ]. Since HIF-1α degradation is triggered by oxygen-sensitive hydroxylation of two conserved proline residues by HIF-prolyl-hydroxylases, inhibition of the latter may enforce SDF-1 and CXCR4 gene expression and stimulate cardiac repair in the ischemic heart. In line with that assumption, a recently published study suggests that early activation of CXCR4 in cardiomyocytes after a single intramyocardial injection of the HIF-prolyl-hydroxylase inhibitor DMOG improved myocardial function by preventing cardiomyocyte cell death [ 12 ]. However, this study neither analyzed HIF-1α activation and SDF-1 expression nor investigated recruitment of CXCR4+ cells from the bone marrow (BM) and heart. Therefore, we hypothesized that DMOG-induced PH inhibition may activate SDF-1 expression to augment CXCR4+ cell recruitment for cardiac repair.