Smith Camilla, Halvorsen Bente, Otterdal Kari, Waehre Torgun, Yndestad Arne, Fevang Børre, Sandberg Wiggo J, Breland Unni M, Frøland Stig S, Oie Erik, Gullestad Lars, Damås Jan K, Aukrust Pål
Research Institute for Internal Medicine, Rikshospitalet Medical Center, University of Oslo, Oslo, Norway.
Cardiovasc Res. 2008 Jul 1;79(1):195-203. doi: 10.1093/cvr/cvn071. Epub 2008 Mar 13.
CXC ligand 16 (CXCL16) may be involved in inflammation and lipid metabolism, and we hypothesized a role for this chemokine in coronary artery disease (CAD).
We performed clinical studies in CAD patients as well as experimental studies in cells with relevance to atherogenesis [i.e. endothelial cells, vascular smooth muscle cells (SMC), and peripheral blood mononuclear cells (PBMC)]. We also examined the ability of HMG-CoA reductase inhibitors (statins) to modulate CXCL16 levels both in vivo and in vitro. Our main findings were: (i) patients with stable (n = 40) and unstable (n = 40) angina had elevated plasma levels of CXCL16 compared with controls (n = 20); (ii) low-dose simvastatin (20 mg qd, n = 15) and high-dose atorvastatin (80 mg qd, n = 9) down-regulated plasma levels of CXCL16 during 6 months of therapy; (iii) in vitro, atorvastatin significantly decreased the interleukin (IL)-1beta-mediated release of CXCL16 from PBMC and endothelial cells; (iv) attenuating effect of atorvastatin on the IL-1beta-mediated release of CXCL16 in PBMC seems to involve post-transcriptional modulation as well as down-regulation of CXCL16 release through inhibition of the protease a disintegrin and metalloproteinase 10 (ADAM10); (v) soluble CXCL16 increased the release of IL-8, monocyte chemoattractant peptide 1, and matrix metalloproteinases in vascular SMC and increased the release of IL-8 and monocyte chemoattractant peptide 1 in PBMC, with particularly enhancing effects in cells from CAD patients.
Our findings suggest that soluble CXCL16 could be linked to atherogenesis not only as a marker of inflammation, but also as a potential inflammatory mediator.
CXC配体16（CXCL16）可能参与炎症和脂质代谢，我们推测这种趋化因子在冠状动脉疾病（CAD）中发挥作用。
我们对CAD患者进行了临床研究，并对与动脉粥样硬化相关的细胞[即内皮细胞、血管平滑肌细胞（SMC）和外周血单核细胞（PBMC）]进行了实验研究。我们还研究了HMG-CoA还原酶抑制剂（他汀类药物）在体内和体外调节CXCL16水平的能力。我们的主要发现如下：（i）与对照组（n = 20）相比，稳定型心绞痛患者（n = 40）和不稳定型心绞痛患者（n = 40）的血浆CXCL16水平升高；（ii）低剂量辛伐他汀（20 mg qd，n = 15）和高剂量阿托伐他汀（80 mg qd，n = 9）在治疗6个月期间下调了血浆CXCL16水平；（iii）在体外，阿托伐他汀显著降低了白细胞介素（IL）-1β介导的PBMC和内皮细胞中CXCL16的释放；（iv）阿托伐他汀对PBMC中IL-1β介导的CXCL16释放的减弱作用似乎涉及转录后调节以及通过抑制蛋白酶解整合素和金属蛋白酶10（ADAM10）下调CXCL16的释放；（v）可溶性CXCL16增加了血管SMC中IL-8、单核细胞趋化蛋白1和基质金属蛋白酶的释放，并增加了PBMC中IL-8和单核细胞趋化蛋白1的释放，对CAD患者的细胞具有特别增强的作用。
我们的研究结果表明，可溶性CXCL16不仅可作为炎症标志物与动脉粥样硬化相关联，还可作为潜在的炎症介质。
