Antoniades Charalambos, Tousoulis Dimitris, Marinou Kyriakoula, Vasiliadou Carmen, Tentolouris Costantinos, Bouras George, Pitsavos Christos, Stefanadis Christodoulos
Athens University Medical School, 1st Cardiology Department, Hippokration Hospital, Athens, Greece.
Am J Clin Nutr. 2006 Oct;84(4):781-8. doi: 10.1093/ajcn/84.4.781.
Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure.
We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA.
In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading.
Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction.
Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.
高同型半胱氨酸血症是一种与内皮功能障碍及心血管疾病风险增加相关的代谢异常。然而，这些影响的潜在机制尚不清楚。
我们研究了不对称二甲基精氨酸（ADMA）对蛋氨酸诱导的慢性高同型半胱氨酸血症中内皮功能障碍的影响，并评估氧化应激和促炎细胞因子对ADMA释放的调节作用。
在这项双盲、安慰剂对照的平行组研究中，30名受试者（15名高同型半胱氨酸血症患者和15名健康对照）接受蛋氨酸负荷试验，同时给予维生素C（2克）加α-生育酚（800国际单位）组合或安慰剂。在基线及蛋氨酸负荷后4小时测定前臂阻力血管的内皮功能以及ADMA、氧化型低密度脂蛋白（ox-LDL）和促炎细胞因子的浓度。
慢性及蛋氨酸诱导的高同型半胱氨酸血症均与氧化型低密度脂蛋白升高（P<0.01）、促炎细胞因子白细胞介素6表达增加（P<0.05）及内皮功能障碍（P<0.01）相关。虽然急性高同型半胱氨酸血症时ADMA迅速升高（P<0.01），且与蛋氨酸负荷后4小时的前臂充血反应相关（r = -0.722，P = 0.0001），但空腹高同型半胱氨酸水平高的受试者与低水平受试者相比，ADMA水平并未更高。高剂量抗氧化剂治疗可预防蛋氨酸诱导的氧化型低密度脂蛋白和白细胞介素6升高，但未能预防ADMA增加或内皮功能障碍。
慢性及蛋氨酸诱导的高同型半胱氨酸血症均以氧化应激和促炎细胞因子增加为特征，这可能促成内皮功能障碍的发生。然而，ADMA途径仅在急性高同型半胱氨酸血症中被激活，其机制并非由氧化型低密度脂蛋白或促炎刺激介导。
