Abstract 17472: Interruption of Classic CD40L-CD40 Signaling But Not of the Novel CC40L-Mac-1 Interaction Limits Arterial Neointima Formation in Mice
Background: The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. In the light of these data we hypothesized that selective blockade of the CD40L-Mac-1 interaction using our self-designed small peptide inhibitor cM7 - proven to be effective in limiting murine atherosclerosis - may also retard restenosis as assessed by neointima formation in mice.
Methods and Results: We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery, an established model of restenosis. Mice were then randomized to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843µm² vs. 35469 ±11870 µm²), highlighting the importance of CD40 signaling in restenosis.
Conclusion: Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favourable strategy to fight restenosis.
- © 2012 by American Heart Association, Inc.