Abstract 14625: Pharmacological Inhibition of DPP-4 Enhances EPC-Mediated Endothelial Regeneration after Carotid Injury
After deendothelialization of arterial blood vessels the expression of the homing factor SDF-1α by attached platelets, activated endothelial and smooth muscle cells is upregulated via a non-hypoxic induction of hypoxia-inducible factor 1α (HIF-1α). Secreted SDF1α can attract circulating CXCR4+ endothelial progenitor cells via the SDF-1α -CXCR4 axis. Homed progenitor cells can augment endothelial regeneration mainly by paracrine effects. Secreted SDF-1α is cleaved by the serine protease DPP-4 (CD26). We assessed the hypothesis that the administration of Gliptins (Sitagliptin, Vildagliptin) as pharmacological DPP-4 inhibitors leads to elevated concentrations of local SDF-1α thus improving the homing of G-CSF-mobilized progenitor cells after endothelial injury in a mouse model. We performed an endothelial injury of a defined length of 4 mm in the carotid artery of C57Bl/6 mice by sequential application of a short electric impulse. The animals were then treated with saline (control), G-CSF, a Gliptin or both. According to our endothelial regeneration assay we determined the in vivo reendothelialization 3 days after injury using Evans blue staining prior to the harvest of the injured carotid arteries. To provide proof of our therapeutic principle we used mass spectrometric analyses to verify inhibition of SDF-1α cleavage by the Gliptins. We further investigated the homing of injected DiI-stained bone marrow cells using FACS analysis. The Gliptin-therapy is sufficient to inhibit CD26 activity and therefore to enhance homing of CXCR4+ circulating progenitor cells to sites of endothelial injury. Likewise, the cleavage of SDF-1α was decreased in Sitagliptin-treated mice. Gliptin-treatment leads to a significant increase in endothelial regeneration. Besides the SDF-1α -CXCR4 axis MMP9 activity appears to be helpful in EPC homing. This is the first study to show that DPP4-inhibitors can improve homing of mobilized and circulating progenitor cells into the injured blood vessel wall and therefore augment endothelial healing in a model of carotid injury. Since the class of Gliptins are clinically applicable drugs, our results have direct impact on the transfer of our therapeutic approach from bench to bedside.
- © 2012 by American Heart Association, Inc.