Abstract
Inflammatory mechanisms are involved in the process of atherosclerotic plaque formation and rupture. Accumulating evidence suggests that protease-activated receptor (PAR)-2 contributes to the pathophysiology of chronic inflammation on the vasculature. To directly examine the role of PAR-2 in atherosclerosis, we generated apolipoprotein E/PAR-2 double-deficient mice. Mice were fed with high-fat diet for 12 weeks starting at ages of 6 weeks. PAR-2 deficiency attenuated atherosclerotic lesion progression with reduced total lesion area, reduced percentage of stenosis and reduced total necrotic core area. PAR-2 deficiency increased fibrous cap thickness and collagen content of plaque. Moreover, PAR-2 deficiency decreased smooth muscle cell content, macrophage accumulation, matrix metallopeptidase-9 expression and neovascularization in plaque. Relative quantitative PCR assay using thoracic aorta revealed that PAR-2 deficiency reduced mRNA expression of inflammatory molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. In vitro experiment, we found that PAR-2 deficiency reduced mRNA expression of interferon-γ, interleukin-6, TNF-α and MCP-1 in macrophage under unstimulated and lipopolysaccharide-stimulated conditions. These results suggest that PAR-2 deficiency attenuates the progression and instability of atherosclerotic plaque.
Highlights
Atherosclerosis is the result of a chronic inflammatory response in the arterial wall, which is initiated by the interaction of circulating monocytes with activated endothelial cells, followed by monocytes migration into the intima and subsequent uptake of low-density lipoprotein (LDL) by macrophages and their transformation into foam cells (Danzaki et al, 2012; De Paoli et al, 2014)
To determine whether Protease-activated receptor (PAR)-2 deficiency alters stability of atherosclerotic lesion, plaques in brachiocephalic artery were analyzed for features which associated with plaque stability, such as fibrous cap thickness, collagen content, smooth muscle cell (SMC) content, macrophage content, and neovascularization (Fenning and Wilensky, 2014)
The result of immunostaining against Mac-2 revealed that PAR-2 deficiency significantly reduced accumulation of macrophage in atherosclerotic plaque compared to the control group (Figure 2B)
Summary
Atherosclerosis is the result of a chronic inflammatory response in the arterial wall, which is initiated by the interaction of circulating monocytes with activated endothelial cells, followed by monocytes migration into the intima and subsequent uptake of low-density lipoprotein (LDL) by macrophages and their transformation into foam cells (Danzaki et al, 2012; De Paoli et al, 2014). Accumulating evidence suggests that pro-inflammatory cytokines such as interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1 can promote the atherosclerotic plaque destabilization in apolipoprotein E-deficient (ApoE−/−) mice (Inoue et al, 2002; Koga et al, 2007; Alexander et al, 2012). Inflammation increased PAR-2 expression in endothelial cells (Nystedt et al, 1996; Hezi-Yamit et al, 2005), in turn, PAR-2 activation promotes the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IFN-γ, IL-8 and IL-18 in the endothelium (Ikawa et al, 2005). We found that, PAR-2 activation promotes the expression of pro-inflammatory cytokines IL-6, IL-8, TNF-α and IFN-γ in macrophage, a key player in the progression and destabilization of atherosclerotic plaque (Zuo et al, 2015b). In the present study, we aim to assess the effects of PAR-2 on the development and stability of atherosclerotic plaque by using mice that completely lack PAR-2 (PAR-2−/−) by crossing them with ApoE−/− mice, which is the most common mice model for human atherosclerotic disease
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