首頁 > 期刊首頁 > 生理學報 > 2005年2期 > 血漿同型半胱氨酸水平升高與動脈粥樣硬化
血漿同型半胱氨酸水平升高與動脈粥樣硬化
Hyperhomocysteinemia and atherosclerosis
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- 摘要：
- 心血管疾病已成為當今全球性致殘與致死的最重要原因之一.目前確定的冠心病的危險因素主要包括高齡、血脂異常、高血壓、糖尿病、吸煙、肥胖癥.大量的臨床試驗及流行病學研究已經證實血漿同型半胱氨酸水平升高是心血管疾病的一個獨立的危險因素.健康人的血漿同型半胱氨酸水平為5～10 μmol/L.血漿同型半胱氨酸水平嚴重升高的主要原因是胱硫醚-β-合成酶(cystathionine-β-synthase,CBS)基因的缺陷.CBS基因缺陷的純合體可導致血漿同型半胱氨酸水平升高至100～500umol/L.血漿同型半胱氨酸水平嚴重升高的病人通常伴隨神經系統異常、早發性的動脈粥樣硬化.葉酸、維生素B6和B12治療能降低血漿同型半胱氨酸的水平并改善血管內皮功能、減少經皮冠狀動脈腔內成形術(percutaneous transluminal coronary angioplasty,PTCA)術后并發癥.迄今為止,血漿同型半胱氨酸水平升高引起心血管疾病的發病機制并未完全明了,目前認為主要與以下幾個方面有關:(1)內皮細胞損傷及功能障礙.我們實驗室在CBS基因敲除的小鼠模型上證實血漿同型半胱氨酸水平升高能抑制eNOS的活性,導致主動脈內皮功能的障礙.我們還在細胞模型上證實了同型半胱氨酸能顯著抑制內皮細胞的增殖.(2)膽固醇和甘油三脂生物合成代謝異常.我們實驗室在apoE、CBS雙基因敲除的小鼠模型上證實血漿同型半胱氨酸水平升高能改變肝臟的脂肪代謝,增加巨噬細胞對修飾LDL的攝取,從而導致膽固醇脂和甘油三脂在血管壁的堆積,促進主動脈粥樣斑塊的形成.(3)刺激血管平滑肌細胞增殖.此外還發現同型半胱氨酸能激活蛋白激酶C信號途徑,促進膠原蛋白的合成,抑制彈性蛋白和膠原蛋白的交聯.(4)激活血栓形成.(5)激活單核細胞.目前認為同型半胱氨酸主要通過以下幾個化學機制致病:(1)自氧化產生活性氧.同型半胱氨酸在自氧化的過程中能產生大量的活性氧,從而引起血液中脂蛋白和細胞膜脂質的過氧化損傷,并進一步引起內皮功能的障礙.(2)在腺苷的參與下形成SAH,一種甲基轉移抑制劑,導致細胞內的低甲基化.(3)與一氧化氮結合形成亞硝酰物.(4)參與蛋白質的合成.總之,我們和其他實驗室的研究結果均表明同型半胱氨酸不僅與動脈粥樣硬化相關,而且具有致病效應.盡管補充葉酸、維生素B6和B12等治療能降低血漿同型半胱氨酸的水平,但是否能降低心血管疾病的風險仍有待于大量的動物研究及臨床試驗.
- Abstract：
- Arteriosclerosis and its complications, such as heart attack and stroke, are the major causes of death in developed countries.It was believed that age, hyperlipidemia, hypertension, diabetes and smoking are common risk factors for cardiovascular disease. In addition, overwhelming clinical and epidemiological studies have identified homocysteine (Hcy) as a significant and independent risk factor for cardiovascular disease. In healthy individuals, plasma Hcy is between 5 and 10 μmol/L. One cause of severe hypehomocys-teinemia (HHcy) is the deficiency of cystathionine β-synthase (CBS), which converts Hcy to cystathionine. CBS homozygous deficiency results in severe HHcy with Hcy levels up to 100 to 500 μmol/L. Patients with severe HHcy usually present with neurological abnormalities, premature arteriosclerosis. It has been reported that lowering plasma Hcy improved endothelial dysfunction and reduced incidence of major adverse events after percutaneous coronary intervention. The mechanisms by which Hcy induces atherosclerosis are largely unknown. Several biological mechanisms have been proposed to explain cardiovascular pathological changes associated with HHcy. These include: (1) endothelial cell damage and impaired endothelial function; (2) dysregulation of cholesterol and triglyceride biosynthesis; (3) stimulation of vascular smooth muscle cell proliferation; (4) thrombosis activation and (5) activation of monocytes. Four major biochemical mechanisms have been proposed to explain the vascular pathology of Hcy. These include: (1) autooxidation through the production of reactive oxygen species; (2) hypomethylation by forming SAH, a potent inhibitor of biological transmethylations; (3) nitrosylation by binding to nitric oxide or (4) protein homocysteinylation by incorporating into protein. In summary, our studies, as well as data from other laboratories support the concept that Hcy is causally linked to atherosclerosis, and is not merely associated with the disease. Although folic acid, vitamin B12 and B6 can lower plasma Hcy levels, the long-term effects on cardiovascular disease risk are still unknown and judgments about therapeutic benefits await the findings of ongoing clinical trials.
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