CD26 Inhibition Enhances Perfusion Recovery in ApoE-/-Mice

Rene      T. Haverslag; Daphne      de Groot; Sebastian      Grundmann; Benjamin      Meder; Marie-Jose      Goumans; Gerard      Pasterkamp; Imo      E. Hoefer; Dominique      P.V. de Kleijn

Abstract

Objective: The adaptive growth of blood vessels is important to prevent tissue loss following arterial occlusion. Extravasation of monocytes is essential for this process. The peptidase CD26 targets SDF-1 alpha, a chemokine regulating monocyte trafficking. We hypothesized that blocking SDF-1 alpha inactivation, using a commercially available CD26 inhibitor, accelerates perfusion recovery without detrimental side effects on plaque stability. Methods and Results: Atherosclerosis prone ApoE-/- mice underwent femoral artery ligation and received a CD26 inhibitor or placebo. CD26 inhibition increased short term (7 days) perfusion recovery after both single and daily doses compared to placebo, 36%±2 (p=0.017) and 39%±2 (p=0.008) vs. 29%±3 respectively. Long term (56 days) perfusion recovery increased after daily treatment compared to placebo 83%±3 vs. 60%±2, (p<0.001). CD26 inhibition did not result in increased atherosclerotic plaque instability or inflammatory cell infiltration. CD26 inhibition increased macrophage number around growing collaterals, SDF-1 alpha plasma levels and monocyte expression of the activation marker CD11b and the SDF-1 alpha receptor CXCR-4. Conclusions: CD26 inhibition enhanced perfusion recovery following arterial occlusion via attenuated SDF-1 alpha inactivation and increased monocyte activation. There was no observable aggravation of atherosclerosis and CD26 inhibition could therefore offer a novel approach for therapeutic arteriogenesis in patients.

Keywords: CD26, collateral circulation, leukocytes, perfusion recovery, SDF-1 alpha, monocyte activation

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