Chemokine receptor CCR5: from AIDS to atherosclerosis

Abstract

There is increasing recognition of an important contribution of chemokines and their receptors in the pathology of atherosclerosis and related cardiovascular disease. The chemokine receptor CCR5 was initially known for its role as a co-receptor for HIV infection of macrophages and is the target of the recently approved CCR5 antagonist maraviroc. However, evidence is now emerging supporting a role for CCR5 and its ligands CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) in the initiation and progression of atherosclerosis. Specifically, the CCR5 deletion polymorphism CCR5delta32, which confers resistance to HIV infection, has been associated with a reduced risk of cardiovascular disease and both CCR5 antagonism and gene deletion reduce atherosclerosis in mouse models of the disease. Antagonism of CCL5 has also been shown to reduce atherosclerotic burden in these animal models. Crucially, CCR5 and its ligands CCL3, CCL4 and CCL5 have been identified in human and mouse vasculature and have been detected in human atherosclerotic plaque. Not unexpectedly, CC chemokines have also been linked to saphenous vein graft disease, which shares similarity to native vessel atherosclerosis. Distinct roles for chemokine-receptor systems in atherogenesis have been proposed, with CCR5 likely to be critical in recruitment of monocytes to developing plaques. With an increased burden of cardiovascular disease observed in HIV-infected individuals, the potential cardiovascular-protective effects of drugs that target the CCR5 receptor warrant greater attention. The availability of clinically validated antagonists such as maraviroc currently provides an advantage for targeting of CCR5 over other chemokine receptors.

Prevalence of CCR5-Δ32 and CCR2-V64I polymorphisms in a mixed population from northeastern Brazil

“…Since their initial characterization, CCR5-D32 and CCR2-V64I polymorphisms have become attractive candidates for genetic association studies of various diseases, particularly those examining the circulatory system and neoplasms (Jones et al, 2011;Lin et al, 2012;Kucukgergin et al, 2012;Tanyel et al, 2013;Zambra et al, 2013). However, for complex diseases, the actual clinical relevance of these polymorphisms remains inconclusive and studies have shown conflicting results (Vázquez-Lavista et al, 2009;Kucukgergin et al, 2012).…”

HIV, Inflammation, and Calcium in Atherosclerosis

“…An abundance of chemokines (eg, C-X-C chemokine ligand [CXCL]-12, chemokine ligand [CCL]-and MCP1) have also been detected in atherosclerotic lesions and are known to be crucial in directing recruitment of monocytes and T cells. 36 Of note, some of these chemokines are also primary ligands to the major coreceptors for HIV entry, specifically C-X-C chemokine receptor (CXCR)-4 and CCR5. Interestingly, a 32-bp deletion in the CCR5 sequence results in a nonfunctional gene, and homozygous individuals are resistant to HIV infection.…”

Kruppel-like factor 15 is critical for vascular inflammation

“…These larger Klf15 -/-carotid lesions had a 24% ± 7% greater prevalence of macrophages (n = 6, P < 0.001), but fewer VSMCs (50% ± 20%) than were observed in the WT carotid lesions ( Figure 2C and data not shown). To understand why Klf15 -/-carotid interposition grafts recruited more macrophages, we first isolated VSMCs from WT and KLF15-null aortae and tested protein expression levels of a panel of proinflammatory and proatherosclerotic targets by ELISA (12,(16)(17)(18)(19)(20)(21)(22)(23)(24). Of the 22 targets tested, 6 targets were significantly increased, including monocyte chemotactic protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), matrix metalloproteinase 3 (MMP3), PDGFAA, and PDGFAB ( Figure 2D), while VEGF levels were significantly lower in KLF15-null VSMCs.…”