Abstract 17430: Cd44 Contributes to the Development of Abdominal Aortic Aneurysm in Mice Through the Interaction With Hyaluronic Acid and the Recruitment of Macrophages
Background: Abdominal aortic aneurysm (AAA) is a common disease characterized by mobilization of inflammatory cells into vessel walls and activation of vascular cells, leading to degradation of extracellular matrix(ECM). CD44 is not only a principle receptor for hyaluronic acid (HA), but also an adhesion molecule expressed on inflammatory and vascular cells. Recently, we have reported that low-molecular weight HA induced inflammatory cytokines from human peripheral mononuclear cells. We investigated the potential role of CD44 in the development of AAA.
Methods: For induction of AAA, we applied 0.5 M CaCl2 to the infrarenal aortae of mice deficient for CD44, and wild type (WT) littermates as a control.
Results: Six week after application of CaCl2, the diameter of aorta in CD44−/−mice (12%±13%, n=8) was significantly smaller than that in WT mice (53%±12%, n=10). The elevated expression of matrix metalloproteinase (MMP)-2, -9, -12 and monocyte chemotactic protein-1 in WT aorta at one week after CaCl2 treatment were significantly ameliorated in CD44−/−mice. The recruitment of macrophages to AAA lesion in WT mice was found to be significantly greater than that in CD44−/−mice. Furthermore, we assessed HA metabolism in AAA lesion. One week after application of CaCl2, the increased expression of hyaluronidase 1 and the decreased expression of hyaluronan synthase 2 were observed in WT mice. Electrophoresis also showed the increased in smaller size HA in AAA. The expression of CD44 was also shown to be increased in AAA lesion of WT mice. Finally we demonstrated that low-molecular weight proinflammatory forms of HA, but not high-molecular-weight HA, stimulated MMP-9 production in peritoneal macrophages and vasuclur smooth mucsle cells from WT mice, considerably more than those from CD44−/−mice.
Conclusions: Targeted deletion of CD44 resulted in attenuation of AAA development. The interaction of low-molecular weight HA on CD44 may augment inflammatory response and degradation of ECM in AAA lesion.CD44 plays a pivotal role in the progression of AAA through multiple mechanisms.
- © 2010 by American Heart Association, Inc.