Pruefer D, Scalia R, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Gen Pharmacol. 1999 Dec;33(6):487-98. doi: 10.1016/s0306-3623(99)00045-2.
Recent evidence indicates that chronic hyperhomocysteinemia, which is found in from 9 to 15% of the general population, is an independent risk factor for the development of atherosclerosis. We sought to elucidate the mechanism by which exposure of the vascular wall to high levels of homocysteine initiates this inflammatory reaction. We examined the acute effect of homocysteine on endothelial dysfunction in isolated rat arteries and on microcirculatory leukocyte-endothelium interaction in vivo. Intravital microscopy of rat mesenteric venules was performed by superfusing the mesentery with increasing concentrations of homocysteine (1-5 mmol/l). There was a significant concentration- and time-dependent increase in leukocyte rolling, adherence, and extravasation compared with control rats superfused with Krebs-Henseleit solution (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly increased P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression on intestinal venules after homocysteine superfusion. In contrast, mesenteric superfusion with the nitric oxide donor 4-hydroxymethyl-furazan-3-carboxylic acid oxide (CAS1609, 1 micromol/l) significantly attenuated homocysteine-induced leukocyte rolling, adherence, and transmigration to control levels (p < 0.01). CAS1609 also attenuated both P-selectin and ICAM-1 expression on mesenteric venules and decreased CD18 expression on isolated leukocytes. Superior mesenteric arteries incubated with 5 mmol/l homocysteine developed significant (p < 0.01) endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent dilators). Acute hyperhomocysteinemia induces endothelial dysfunction, characterized by a loss of endothelium-derived nitric oxide, leading to an inflammatory state. This state results in increased leukocyte rolling, adherence, and transmigration by upregulation of cell adhesion molecules. Our data suggest that hyperhomocysteinemia inhibits the important homeostatic role of nitric oxide in preventing endothelial dysfunction.
近期证据表明，在9%至15%的普通人群中发现的慢性高同型半胱氨酸血症是动脉粥样硬化发生的独立危险因素。我们试图阐明血管壁暴露于高水平同型半胱氨酸引发这种炎症反应的机制。我们研究了同型半胱氨酸对离体大鼠动脉内皮功能障碍以及体内微循环白细胞与内皮细胞相互作用的急性影响。通过用浓度递增的同型半胱氨酸（1 - 5 mmol/L）灌注肠系膜来对大鼠肠系膜小静脉进行活体显微镜观察。与用克雷布斯 - 亨塞尔特溶液灌注的对照大鼠相比，白细胞滚动、黏附和渗出有显著的浓度和时间依赖性增加（p < 0.01）。此外，免疫组化染色显示同型半胱氨酸灌注后肠小静脉上P选择素和细胞间黏附分子 -1（ICAM -1）表达显著增加。相比之下，用一氧化氮供体4 - 羟甲基 - 呋咱 -3 - 羧酸氧化物（CAS1609，1 μmol/L）灌注肠系膜可使同型半胱氨酸诱导的白细胞滚动、黏附和迁移显著减轻至对照水平（p < 0.01）。CAS1609还可减轻肠系膜小静脉上P选择素和ICAM -1的表达，并降低离体白细胞上CD18的表达。用5 mmol/L同型半胱氨酸孵育的肠系膜上动脉出现显著（p < 0.01）的内皮功能障碍（即对内皮依赖性舒张剂的舒张功能受损）。急性高同型半胱氨酸血症诱导内皮功能障碍，其特征是内皮源性一氧化氮丧失，导致炎症状态。这种状态通过上调细胞黏附分子导致白细胞滚动、黏附和迁移增加。我们的数据表明，高同型半胱氨酸血症抑制了一氧化氮在预防内皮功能障碍中的重要稳态作用。
