三基因突变小鼠血脂代谢及动脉粥样硬化早期病变特征

The characteristics of atherosclerotic early lesion in treble lipid metabolism genes mutant mouse

目的研究血脂代谢相关基因与瘦素受体基因联合突变导致小鼠血脂代谢紊乱的发生机制和动脉粥样硬化早期病变的特点及两者间的关系。方法应用生物化学及组织形态学手段对三基因突变(apoE-/-/LDLR-/-/Leprdb/db)与双基因突变(apoE-/-/LDLR-/-)小鼠和单基因突变(Leprdb/db)小鼠之间血脂及动脉粥样硬化早期病变的差异进行了比较研究。结果三基因突变小鼠3周龄时血浆总胆固醇、甘油三酯和血糖浓度分别为(1988±190)、(293±029)和(727±088)mmol/L,均高于双基因和单基因突变小鼠,同时出现轻微的主动脉内膜损伤,血脂及动脉粥样硬化程度随年龄增长而加重。11周龄三基因突变小鼠血浆总胆固醇、甘油三酯和血糖水平分别高出双基因突变小鼠166、141和24倍,且动脉内膜病变较双基因和单基因突变小鼠明显,其严重程度与血脂紊乱正相关。结论三个脂代谢相关基因联合突变在导致小鼠血脂代谢紊乱及主动脉粥样硬化病变的发生发展中起重要作用。

Objective To clarify the effects of polygenetic disfunction in lipid metabolism and atherogenesis in the mutant mice. Methods Treble lipid metabolic gene mutant (apoE -/- /LDLR -/- /Lepr db/db ) mice has been established and a comparative analysis was done with the mice of other lipid metabolism related gene mutants, including double gene mutant (apoE -/- /LDLR -/- ) and single gene mutants (apoE -/- , LDLR -/- and Lepr db/db ) mice, by using biochemical and pathological techniques. Results A various significant elevation in plasma level of total cholesterol (TC), triglyceride(TG) and glucose was found with progressing of time at 3 week old young treble gene mutant mice. They reached (19 88±1 90), (2 93±0 29)and (7 27±0 88)mmol/L, respectively, and higher than those in double and signal gene mutants . The apoE -/- /LDLR -/- /Lepr db/db mice was accompanied by endothelial edema, endothelial deciduation in local area at this age. In addition, other atherosclerotic lesions such as monocyte/macrophage infiltration and adhere/enter to subendothelium, foam cell formation, rupture of inner elastic lamina and intimal thickness by accumulation and proliferation of smooth muscle cells and extracellular matrix were found in local regions of aortic root and arch areas from 7 11week old treble gene mutants. The atherosclerotic lesions were progressing with age until the time point of investigation and related positively with the levels of TC and TG. Conclusion Treble lipid metabolic gene mutant (apoE -/- /LDLR -/- /Lepr db/db ) were highly contributed to hyperlipidemia and process of atherogenetic lesions in the young mutants. Our data indicated that lipid metabolism related polygenetic mutation was a more critical key risk factor than those of double and signal gene disfunction during atherogenesis development.