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Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation. [ABSTRACT FROM AUTHOR]

Abstract: Background: We sought to examine if polymorphisms in the promoter region of YKL-40 gene (CHI3L1) are associated with serum YKL-40 levels and coronary artery disease (CAD) in Chinese patients. Methods: Three single nucleotide polymorphisms (SNPs) (−329G>A, rs10399931; −247C>T, rs10399805; −131G>C, rs4950928) in the CHI3L1 promoter were determined in 213 consecutive patients with angiographically documented CAD (luminal diameter stenosis ⩾50%) and 248 normal controls. Coronary cumulative obstruction score and number of diseased vessels represent the severity of CAD. Serum YKL-40 levels were assessed using an ELISA kit. Results: Patients with CAD had remarkably higher serum YKL-40 levels compared to controls (p <0.001). There was no difference in the allele, genotype and haplotype distribution of these three SNPs between controls and CAD patients. The minor alleles of CHI3L1−329G>A and −131G>C were significantly associated with decreased serum YKL-40 levels in both controls (p =0.001 and p <0.001, respectively) and CAD patients (p =0.007 and p <0.001, respectively), whereas CHI3L1−247C>T had no appreciable effect. None of these genetic variants and haplotypes was associated with severity of angiographic CAD. Conclusions: CHI3L1−329G>A and −131G>C polymorphisms are associated with serum YKL-40 levels, but not with the prevalence or severity of CAD. [Copyright &y& Elsevier]