CD26 inhibition enhances perfusion recovery in ApoE-/-mice

Curr Vasc Pharmacol. 2013 Jan;11(1):21-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • CD11b Antigen / metabolism
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Femoral Artery / metabolism*
  • Femoral Artery / pathology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Ligation / methods
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Monocytes / metabolism
  • Perfusion / methods
  • Receptors, CXCR4 / metabolism

Substances

  • Apolipoproteins E
  • CD11b Antigen
  • Chemokine CXCL12
  • Receptors, CXCR4
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse