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CD36、磷脂蛋白與動脈粥樣硬化

來源:中華醫學研究雜志 作者:張建社 2006-12-18

摘要: CD36、磷脂蛋白與動脈粥樣硬化(pdf) 【摘要】 動脈粥樣硬化是嚴重影響人類健康的疾病之一。它發生的機理被認為主要是由于膜受體CD36與低密度磷脂蛋白結合形成泡沫細胞沉積血管內壁所致,本文簡要地對CD36的結構與功能,低密度蛋白特性和形成與動脈粥樣硬化的關系進行了綜述和討論分析,為進一步深化對該疾病的發生機理和......


  CD36、磷脂蛋白與動脈粥樣硬化(pdf)

    【摘要】  動脈粥樣硬化是嚴重影響人類健康的疾病之一。它發生的機理被認為主要是由于膜受體CD36與低密度磷脂蛋白結合形成泡沫細胞沉積血管內壁所致,本文簡要地對CD36的結構與功能,低密度蛋白特性和形成與動脈粥樣硬化的關系進行了綜述和討論分析,為進一步深化對該疾病的發生機理和預防提供理論依據。   

  【關鍵詞】  CD36;oxLDL;動脈粥樣硬化;膜受體   

  CD36,oxLDL and atherosclerosis

  ZHANG Jian-she.

  Department of Bioengineering and Environmental Science, Changsha University, Changsha,Hunan  410003,China

  【Abstract】  Atherosclerosis is one of the serious diseases to human and it is mainly caused by the interaction of a scavenger gene family member, membrane receptor CD36 and lipoprotein, oxLDL to form foam cells in the sub-endothelial space of the involved vessel. In this article, the molecular characteristics and physiological functions of CD36 and oxLDL as well as their relation to the occurrence of atherosclerosis were briefly reviewed and analyzed. The information provides us to a better understanding of the mechanism of atherosclerosis and the pervention for the disease.

  【Key words】  CD36;oxLDL; atherosclerosis; receptor    

  動脈粥樣硬化(Atherosclerosis)是嚴重影響人類健康的疾病之一。近年來,隨著心腦血管發病率逐年增高的趨勢,對于動脈粥樣硬化產生的機理已成為醫學界和生物界廣為研究的熱門課題。綜合已有研究成果證實,歸屬于清道夫(Scavenger)家族成員之一的CD36和低密度氧化脂蛋白(oxCDL)與動脈粥樣硬化疾病發生緊密相關[1, 2]。因此,本綜述擬對CD36和oxDL的生物學特性和生理功能以及與動脈粥樣硬化發生進行綜合分析,為進一步開展對該疾病的研究和預防提供理論依據。

  1  CD36結構與功能

  CD36屬一種多功能細胞膜受體,直接影響動脈粥樣硬化的形成。它于1976年首次被發現并被歸屬于一種抗蛋白酶血小板膜表面糖蛋白,并根據它在SDS-PAGE電泳所獲分子量而命名為糖蛋白Ⅳ,由于它與白細胞分化抗原CD36相似,因此而得名[3]。CD36是一類分子量為88kDa的細胞表面糖蛋白,廣泛在單核細胞、巨噬細胞、內皮層細胞、血小板、紅細胞前板、脂肪細胞、肌肉細胞以及乳腺內皮層細胞中發現[4,5]。并且CD36與溶酶體膜結合蛋白(LIMPⅡ)、清道受體B1(SRB1)以及CLA1共同構成一類新的基因家族[6,7]。CD36蛋白為多肽單鏈,包含有兩個跨膜區域(Transmembrane domains), 且此兩區域具有棕櫚酰化(Palmitoylated)半胱氨酸殘基[8]。CD36肽鏈兩個硫水末端作為與細胞膜結合支柱外,且兩末端的最后10個氨基酸位于胞內,其余部分則暴露于細胞膜外周稱為外周部分(extracellular segment)。它膜外周區行使功能結構,具有許多受體結合部分,并具多個N-連接的糖苷化為點, 且C-末端可能參與受體激酶(kinase)調節的信息傳導作用[9]。   
  CD36作為膜蛋白復合受體,與多種配體結合,行使不同生物功能。這些配位體主要包括阿米巴傳染的血紅細胞[10~12],膠原蛋白類型Ⅰ和Ⅳ[13],血小板反應蛋白(TSP)[14], 血小板凝集因子P37[15]以及Src家族蛋白激酶調節相關的信號傳導因子[9]。此外,CD36還參與長鏈脂肪酸的吸附和調節細胞凋亡殘物的清理和巨噬細胞的吞噬作用等[16, 17]。研究結果證實,上述這些配體在CD36肽鏈具有特異結合位點,如TSP結合位點為肽鏈氨基酸93-120, pRBC為145-184,凋亡細胞結合位點為155-183,以及oxLDL為28-93[18, 19]。

  2  CD36與脂蛋白oxLDL  

  已有研究證實,有A、B、C三類對脂蛋白oxLDL結合的受體,其中A類包括乙酰化低密度受體(AcLDL),并且AcLDL受體分別能與oxLDL、AcLDL和一些多聚陰離子配體結合。C類受體與A類基本相似,但幾乎僅在果蠅胚胎巨噬細胞中發現[20]。Endeman等和Acton等采用COS7細胞表達克隆鑒定出一類對oxLDL高密度親和的受體,歸屬于B類,包括CD36和SR-B1。類似A和C類受體,B類受體能與oxLDL和AcLDL高度親和,但與A和B類不同的是能與負性的磷脂反應。oxLDL一旦與CD36結合后,迅速被CD36蛋白內卷(internalization)[21~23]。此外,人類的巨噬細胞的CD36既能與修飾的LDL(oxLDL和AcLDL),還與尚未修飾的磷蛋白(LDL,HDL和VLDL)高度親和[24]。CD36基因敲除的巨噬細胞對oxLDL的結合和內包以及降解能力顯著減弱,因此細胞膽固醇脂類的沉積也明顯降低[25]。這些結果說明,CD36是主要的oxLDL受體并且對脂肪的沉積和代謝起著重要的調節作用。

  3  oxLDL與動脈粥樣硬化  

  動脈粥樣硬化最早可見的癥狀是負荷脂類的巨噬細胞在血管內壁形成,這類細胞稱為泡沫狀細胞(foam cells)[25~27]。實驗研究證實,oxLDL明顯沉積在動脈粥樣硬化的病灶內,但在正常的動脈血管內沒有發現。未經修飾的脂蛋白(LDL、HDL)以及氧化的脂蛋白(oxLDL)在動脈壁管內的沉積作用在有脂蛋白酶(Lipase)的作用下而增強,這可能是動脈粥樣硬化產生的重要環節[28,29]。從許多動物的研究中發現,抗氧化劑如Probucal能降解低或緩解動脈粥樣硬化的發生發展[30]。  

  oxLDL除促進巨噬細胞膽固醇的沉積以外,還參與其它致使動脈硬化產生途徑。oxLDL對細胞具有一定毒力作用(toxic),可致使由于氮氧化物(Nitric oxide)的釋放受阻而引起內壁細胞損傷[31, 32]。同時,oxLDL還對單核細胞具有趨化作用以及對巨噬細胞遷移的阻礙作用[33, 34]。oxLDL的氧化盡管是低度的,仍能誘導巨噬細胞克隆刺激因子,單核細胞趨化蛋白因子和一些組織因子的表達,而直接或間接影響動脈粥樣硬化產生[35]。此外,oxLDL還能在內壁細胞吸附分子如VCAM-1的表達和誘導細胞凋亡過程發生[36, 37]。上述這些過程均能導致單核細胞和巨噬細胞的聚集和滯留,最終導致動脈粥樣硬化的發生。

  4  導致脂蛋白氧化的因素    

  磷脂蛋白包括有磷脂、游離膽固醇、膽固醇乙脂、甘油酯等所有這些都有可能被氧化。LDL在實驗室條件下可被金屬離子如Cu+和Fe+氧化[38],但此過程一般不含在體內條件下發生。這類金屬離子可能仿效生物學上產生的氧化元素如OH和O2而起作用[39]。目前,體內LDL氧化因子尚未定義,但推測可能包括以下種類,如由白細胞產生的游離基和超氧化物[40]、酯加氧酶(Lipoxygenase)。如在巨噬細胞和內壁細胞中發現的15-酯加氧酶[41],在單核細胞和嗜中性粒細胞中的髓過氧化物酶(Myeloperoxidase)[42],與糖尿病發生中葡萄糖水平增加時糖氧化物作用(glycoxidation)以及活性氧的中間物等[43]。在具有抗氧化因子,如維生素-E ,β-Carotene和ubiquinol 的條件下, 磷脂蛋白(LDL)的氧化一般不易發生[44, 45]。

  5  小結   

  動脈粥樣硬化是一種廣泛性疾病,嚴重威脅人類健康和生活質量。因此,對于該病發生發展的機理以及治療方法的研究已引起高度重視。大量研究證實,CD36作為清道夫受體家族成員之一,通過它與氧化低密度磷脂的特異結合和沉積,導致以海綿細胞形成為病灶的動脈粥樣硬化的產生。近期采用CD36基因敲除的白鼠為模式動物實驗,直接證實CD36對動脈硬化產生的作用[46]。采用骨髓移植技術,將CD36基因缺陷的骨髓移植到apoE-缺陷的老鼠,動脈粥樣硬化發生降低70%~80%[25, 47, 48]。此外CD36還參與脂肪酸的運輸,細胞凋亡殘留物的清除和信號傳導等作用。鑒于CD36的功能多樣性和對心血管疾病發生的緊密相關性,進一步開展對CD36的結構和功能以及與其他細胞因子的偶聯作用以及抗氧化因子的開發研究對于我們有效更深入了解對心血管相關疾病的發生發展機理和制定有效治療方法有著重要意義。

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  (編輯:守  中)

  基金項目:湖南省科技廳05FS3023;長沙市科技創新項目K051127-72

  作者單位: 410003 湖南長沙,長沙學院生物工程與環境科學系   


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