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The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell
C A Cuff1, D Kothapalli, I Azonobi
1The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Insights
CD44 deficiency significantly reduces atherosclerosis in mice by inhibiting inflammatory cell recruitment and smooth muscle cell activation. This highlights CD44
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Adhesion
Background:
- Atherosclerosis, a leading cause of heart attack and stroke, involves inflammatory cell recruitment and vascular cell activation.
- CD44, an adhesion molecule on inflammatory and vascular cells, mediates cell-cell interactions and activation.
- The role of CD44 in atherosclerosis pathogenesis remains to be fully elucidated.
Purpose of the Study:
- To investigate the contribution of CD44 to the development and progression of atherosclerosis.
- To determine the mechanisms by which CD44 influences atherosclerotic lesion formation.
Main Methods:
- Generation of CD44-null mice crossed with apolipoprotein E-deficient (apoE-/-) mice, which are prone to atherosclerosis.
- Quantification of aortic lesion size in CD44-null, heterozygote, and wild-type littermates.
- Assessment of macrophage recruitment, vascular cell activation (VCAM-1 expression), and smooth muscle cell phenotypic changes.
Main Results:
- CD44-null mice exhibited a 50-70% reduction in aortic atherosclerotic lesions compared to controls.
- CD44 deficiency markedly decreased macrophage infiltration into atherosclerotic lesions.
- CD44 was essential for the dedifferentiation of medial smooth muscle cells to a synthetic phenotype, indicated by reduced VCAM-1 expression.
Conclusions:
- CD44 plays a critical role in promoting atherosclerosis progression through multiple pathways.
- Targeting CD44 may offer a novel therapeutic strategy for preventing or treating atherosclerosis.
- The interaction between CD44 and its ligand hyaluronan influences vascular cell behavior in the context of atherosclerosis.
Abstract:
Atherosclerosis causes most acute coronary syndromes and strokes. The pathogenesis of atherosclerosis includes recruitment of inflammatory cells to the vessel wall and activation of vascular cells. CD44 is an adhesion protein expressed on inflammatory and vascular cells. CD44 supports the adhesion of activated lymphocytes to endothelium and smooth muscle cells. Furthermore, ligation of CD44 induces activation of both inflammatory and vascular cells. To assess the potential contribution of CD44 to atherosclerosis, we bred CD44-null mice to atherosclerosis-prone apoE-deficient mice. We found a 50-70% reduction in aortic lesions in CD44-null mice compared with CD44 heterozygote and wild-type littermates. We demonstrate that CD44 promotes the recruitment of macrophages to atherosclerotic lesions. Furthermore, we show that CD44 is required for phenotypic dedifferentiation of medial smooth muscle cells to the "synthetic" state as measured by expression of VCAM-1. Finally, we demonstrate that hyaluronan, the principal ligand for CD44, is upregulated in atherosclerotic lesions of apoE-deficient mice and that the low-molecular-weight proinflammatory forms of hyaluronan stimulate VCAM-1 expression and proliferation of cultured primary aortic smooth muscle cells, whereas high-molecular-weight forms of hyaluronan inhibit smooth muscle cell proliferation. We conclude that CD44 plays a critical role in the progression of atherosclerosis through multiple mechanisms.
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