脂蛋白(a)对转基因家族性高脂血症家兔冠状动脉粥样硬化发生的影响

Influence of Lipoprotein (a) in Transgenic Watanabe Heritable Hyperlipidemic Rabbit's Coronary Atherosclerosis

目的应用载脂蛋白(a)转基因家族性高脂血症家兔模型评价脂蛋白(a)在冠状动脉粥样硬化发展过程中的长期作用结果,以进一步探讨脂蛋白(a)在动脉粥样硬化中的作用机制。方法繁殖人类载脂蛋白(a)转基因家族性高脂血症家兔及同窝生非转基因家族性高脂血症家兔,24月龄,标准普通饲料喂养。测量家兔血浆脂蛋白(a)、总胆固醇、甘油三酯、高密度脂蛋白胆固醇及C反应蛋白水平,组织学染色测量病变内膜面积及狭窄率,并采用免疫组织化学染色分析病变的组成。结果24月龄的转基因家族性高脂血症家兔血浆脂蛋白(a)水平为9.1±3.5nmol/L;转基因与非转基因家族性高脂血症家兔的总胆固醇、甘油三酯和高密度脂蛋白胆固醇水平差异无显著性,但转基因家族性高脂血症家兔右冠状动脉病变面积比非转基因家族性高脂血症家兔高3.5倍(P<0.05)。转基因家兔右冠状动脉的病变大小并没有发生相应的管腔狭窄(狭窄率在非转基因组为26.9%±6.6%,转基因组为27.7%±5.0%),转基因家兔右冠状动脉直径由于血管的代偿性重塑而发生了显著的增加(血管面积在非转基因组为1.8±0.6mm2,转基因组为5.3±1.1mm2;P<0.05)。人类载脂蛋白(a)转基因家兔的病变与载脂蛋白B有关,主要分布在细胞外基质的周围。病变富含细胞外基质,病变中细胞成分所占的比例较少,不足10%。发现有33%转基因家兔及9%非转基因家兔发生了明显的心肌梗死。结论增加血浆脂蛋白(a)水平可加重有高脂血症背景家兔的冠状动脉粥样硬化。

Aim To evaluate the long-term effects of lipoprotein （a） [Lp（a）] on the development of coronary athero-sclerosis in Wabanabe heritable hyperlipidemic （WHHL） rabbits, to further study the mechanism of Lp（a） in the process of ather-oscleresis. Methods Generated human apolipoprotein （a） [apo（a）] transgenic（Tg） WHHL rabbits were compared with non-Tg WHHL rabbits aged24 months （fed a standard chow diet） . Plasma levels ofLp （a）, totalcholesterol （TC）, triglyceride （TG）, high density lipoproteins cholesterol （HDLC） and plasma levels of C-reactive protein （CRP） were measured using the methods. Area of intimal lesion and stenosis degree were measured by histologically staining and the components in the lesions were analyzed using staining. Result Tne mean levels of human Lp（a） in Tg rabbit plasma were 9.1±3.5 nmol/L at 24 months. Compared to non-Tg WHHL rabbits, Tg WHHL rabbits did not show significant changes in plasma TC, TG, or HDLE. However, Tg WHHL rabbits showed 3.5-fold increased lesions in right coronary arteries than non-Tg WHHL rabbits （ P 〈 0.05 ）. Increased lesion size in RCA of Tg WHHL rabbits did not result in a proportional increase of lumen stenesis in RCA （26.9±6.6% in non-Tg vs 27.7 ± 5.0% in Tg）, suggesting that componsational remodeling occurred as the diameter of RCA ofTg WHHL rabbits were markedly increased （1.8±0.6 mm^2 in non-Tg vs 5.3±1.1 mm^2 in Tg, P〈0.05）. Human apo （a） immuno-reactive proteins were focally present in the lesions of Tg WHHL rabbits and associated with apolipopro-tein B, but mainly located around the extraceUular matrix rather than associated with macrophages. Cellular components accounted for less than 10% of the lesions and there were no difference between non-Tg and Tg WHHL rabbits. Three Tg rabbits （33%） and one non-Tg WHHL rabbits （9%） which had apparently extensive myocardial infarction lesions were detected.Conclusion Increased plasma levels of Lp（a） enhance the coronary atherosclerosis in the setting of hypercholesterolemia.