CD44 Expressed on Both Bone Marrow–Derived and Non–Bone Marrow–Derived Cells Promotes Atherogenesis in ApoE-Deficient Mice

Abstract

Objective-The purpose of this study was to distinguish the contributions of CD44 expressed on bone marrow-derived and non-bone marrow-derived cells to atherosclerosis. Methods and Results-Using bone marrow chimeras, we compared the contributions of CD44 expressed on bone marrow-derived cells versus non-bone marrow-derived cells to the vascular inflammation underlying atherosclerosis. We show that CD44 in both bone marrow-derived and non-bone marrow-derived compartments promotes atherosclerosis in apoE Ϫ/Ϫ mice and mediates macrophage and T cell recruitment to lesions in vivo. We also demonstrate that CD44 on endothelial cells (ECs) as well as on macrophages and T cells enhances leukocyte-endothelial cell adhesion and transendothelial migration in vitro. Furthermore, CD44 on vascular smooth muscle cells (VSMCs) regulates their hyaluronan (HA)-dependent migration. Interestingly, in mice lacking CD44 in both compartments, where we observed the least inflammation, we also observed enhanced fibrous cap formation. Conclusions-CD44 expressed on bone marrow-derived and non-bone marrow-derived cells both promote atherosclerosis in apoE-deficient mice. Furthermore, CD44 plays a pivotal role in determining the balance between inflammation and fibrosis in atherosclerotic lesions which can impact clinical outcome in humans. (Arterioscler Thromb Vasc Biol. 2008;28:1283-1289)Key Words: CD44 Ⅲ atherosclerosis Ⅲ apoE Ⅲ bone marrow chimera Ⅲ fibrous cap B oth vascular and inflammatory cells are critical to atherogenesis, but the distinct mechanisms by which these lineages contribute to disease are incompletely understood. Atherosclerosis is initiated by proinflammatory changes in the endothelium caused by insults such as the accumulation of oxidized or other modified lipoproteins and flow-induced mechano-signal transduction. 1,2 The resulting upregulation of endothelial cell (EC) adhesion molecules and production of proinflammatory cytokines and chemokines promotes recruitment of inflammatory cells including monocytes and T cells. 3,4 Vascular injury also promotes vascular remodeling by inducing proliferation and migration of vascular smooth muscle cells (VSMCs). Interestingly, evidence suggests that the balance between the fibrotic response, which promotes the formation of fibrous caps, and the inflammatory response, which inhibits formation of fibrous caps, governs the structure of the atheroma. The overall structure of atheroma in turn determines the susceptibility of plaques to rupture. 5 CD44 is known to be upregulated in human and mouse atherosclerotic lesions and is expressed on all cell types known to play a role in atherogenesis. 6,7 Moreover, ligands for CD44, such as the extra-/pericellular matrix glycosaminoglycan hyaluronan (HA) and osteopontin, accumulate in atherosclerotic lesions. 8,9 We previously demonstrated that CD44-null apoE Ϫ/Ϫ mice develop less extensive atherosclerosis attributable to impaired recruitment of macrophages to atherosclerotic lesions and regulation of vascular smooth muscle cell (VSMC) pro...

Effect of serum amyloid A1 treatment on global gene expression in THP-1-derived macrophages

“…In addition, CD44, which is involved in wound healing, might have other atherogenic roles. CD44 is reported to be involved in the recruitment of macrophages and T cells to atherosclerotic lesions [35], and augmented levels of CD44 are found in macrophages from atherosclerotic subjects [36]. In addition, CD44 also Fold changes between samples obtained from macrophages treated with SAA1 and untreated macrophages were determined using B2M as an internal control for all genes except SERPINB2.…”

Molecular Biology of Atherosclerosis

“…CD44 also binds to hyaluronic acid and promotes leukocyte attachment to endothelium and helps regulate VSMC proliferation. Both bone marrow derived and endothelial or VSMC sources apparently contribute to atherosclerosis (2090).…”

Hyaluronan as a therapeutic target in human diseases

“…Furthermore, CD44 expressed on both bone marrow-derived and non-bone marrow-derived cells promotes atherosclerosis in ApoE-deficient mice through regulating macrophage and T cell recruitment; leukocyte-endothelial cell adhesion and transendothelial migration; and HA-dependent migration of vascular smooth muscle cells [220]. …”