Lin C P, Chen Y H, Lin W T, Leu H B, Liu T Z, Huang S L, Chen J W
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan.
Eur J Clin Invest. 2008 Feb;38(2):106-16. doi: 10.1111/j.1365-2362.2007.01911.x.
Although homocysteine (HCY) is a risk factor for cardiovascular diseases, recent clinical trials failed to show the benefits by reducing plasma HCY. Alternative strategy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, might be feasible. This study investigated HCY-induced endothelial adhesiveness with mononuclear cells (MNCs) from patients with coronary artery disease (CAD). The direct endothelial protective effects of statins were also examined.
Circulating MNCs were isolated from 14 stable CAD patients and 7 age- and gender-matched healthy subjects. Superoxide production of MNCs was determined by Ultra-weak and luminol-enhanced chemiluminescence. Human aortic endothelial cells (HAECs) were used for endothelial adhesiveness to MNCs or U937 human monocytic cells. Endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were examined by Western blot.
Superoxide production of MNCs and plasma HCY and high-sensitive CRP levels were significantly increased in CAD patients than in healthy subjects. Stimulation with HCY enhanced the endothelial adhesiveness to MNCs from CAD patients or to U937 cells in a dose-dependent manner, whereas it was obscure with MNCs from healthy subjects. HCY stimulated endothelial VCAM-1 but not ICAM-1 expression in a dose-dependent manner. Monoclonal antibodies to VCAM-1 attenuated HCY-induced endothelial adhesiveness. Simvastatin or pravastatin significantly reduced HCY-induced VCAM-1 expression and endothelial adhesiveness to MNCs from CAD patients.
Circulating MNCs were activated in CAD patients, which was critical to HCY-induced endothelial adhesiveness. Statins could directly reduce HCY-induced endothelial-MNC adhesion via VCAM-1 inhibition, suggesting its potential implication in HCY-related atherosclerosis disease.
尽管同型半胱氨酸（HCY）是心血管疾病的一个风险因素，但近期的临床试验未能显示出通过降低血浆HCY带来的益处。使用3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）的替代策略可能是可行的。本研究调查了HCY诱导的来自冠心病（CAD）患者的单核细胞（MNCs）与内皮细胞的黏附性。同时也研究了他汀类药物对内皮细胞的直接保护作用。
从14例稳定型CAD患者和7例年龄及性别匹配的健康受试者中分离循环MNCs。通过超微弱和鲁米诺增强化学发光法测定MNCs的超氧化物生成。用人主动脉内皮细胞（HAECs）检测内皮细胞与MNCs或U9-37人单核细胞的黏附性。通过蛋白质印迹法检测血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）的内皮细胞表达。
CAD患者的MNCs超氧化物生成以及血浆HCY和高敏CRP水平显著高于健康受试者。用HCY刺激以剂量依赖方式增强了内皮细胞与CAD患者MNCs或U9-37细胞的黏附性，而与健康受试者的MNCs黏附性不明显。HCY以剂量依赖方式刺激内皮细胞VCAM-1而非ICAM-1的表达。抗VCAM-1单克隆抗体减弱了HCY诱导的内皮细胞黏附性。辛伐他汀或普伐他汀显著降低了HCY诱导的VCAM-1表达以及内皮细胞与CAD患者MNCs的黏附性。
CAD患者的循环MNCs被激活，这对HCY诱导的内皮细胞黏附性至关重要。他汀类药物可通过抑制VCAM-1直接降低HCY诱导的内皮细胞与MNCs的黏附，提示其在HCY相关动脉粥样硬化疾病中的潜在意义。
