Dept. of Chemical Engineering, McGill University, 3610 University Street, Montreal. Qc, H3A 2B2, Canada.
Eur J Pharmacol. 2010 Dec 15;649(1-3):268-76. doi: 10.1016/j.ejphar.2010.09.016. Epub 2010 Sep 19.
In addition to lowering cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been shown to modulate gene expression in endothelial cells. The effect of statins on cell adhesion molecule expression is unclear and largely unexplored in endothelial cells exposed to shear stress, an important regulator of endothelial cell function. In this study, the effect of simvastatin on vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression was evaluated in human abdominal aortic endothelial cells (HAAEC) conditioned with various levels of laminar wall shear stress with or without tumor necrosis factor alpha (TNFα). As expected, TNFα alone greatly enhanced both VCAM-1 and ICAM-1 mRNA and protein. In static culture, simvastatin potentiated the TNFα-induced increase in VCAM-1 and ICAM-1 mRNA but not total protein at 24 h. Mevalonate, a precursor to cholesterol biosynthesis, eliminated the effect of simvastatin. Exposure of endothelial cells to elevated levels of laminar shear stress during simvastatin treatment prevented the potentiating effect of simvastatin on cell adhesion molecule mRNA. A shear stress of 12.5 dyn/cm² eliminated the increase in VCAM-1 by simvastatin, while 25 dyn/cm² was needed for ICAM-1. We conclude that simvastatin enhances VCAM-1 and ICAM-1 gene expression in TNFα-activated endothelial cells through inhibition of HMG-CoA reductase. High levels of laminar shear stress prevented the upregulation of VCAM-1 and ICAM-1 by simvastatin suggesting that an induction of cell adhesion molecules by statins may not occur in endothelial cells exposed to shear stress from blood flow.
除了降低胆固醇，3-羟基-3-甲基戊二酰基辅酶 A（HMG-CoA）还原酶抑制剂，即他汀类药物，已被证明可调节内皮细胞中的基因表达。他汀类药物对细胞黏附分子表达的影响尚不清楚，并且在暴露于剪切应力的内皮细胞中也未得到充分研究，而剪切应力是内皮细胞功能的重要调节剂。在这项研究中，评估了辛伐他汀在人腹主动脉内皮细胞（HAAEC）中的作用，这些细胞在不同水平的层流壁剪切应力下培养，并与肿瘤坏死因子-α（TNFα）共同培养或不共同培养。正如预期的那样，单独的 TNFα 极大地增强了 VCAM-1 和 ICAM-1 的 mRNA 和蛋白表达。在静态培养中，辛伐他汀在 24 小时内增强了 TNFα 诱导的 VCAM-1 和 ICAM-1 mRNA 的增加，但不增加总蛋白。胆固醇生物合成的前体甲羟戊酸消除了辛伐他汀的作用。在辛伐他汀处理过程中，内皮细胞暴露于升高的层流剪切应力下，可防止辛伐他汀对细胞黏附分子 mRNA 的增强作用。12.5 dyn/cm² 的剪切应力消除了辛伐他汀对 VCAM-1 的增加作用，而 ICAM-1 则需要 25 dyn/cm²。我们的结论是，辛伐他汀通过抑制 HMG-CoA 还原酶来增强 TNFα 激活的内皮细胞中 VCAM-1 和 ICAM-1 的基因表达。层流剪切应力水平高可防止辛伐他汀上调 VCAM-1 和 ICAM-1，这表明他汀类药物诱导的细胞黏附分子的表达可能不会发生在血流引起的剪切应力暴露的内皮细胞中。
