间歇低氧促进大鼠动脉粥样硬化机制的研究

Study on the Mechanism of Intermittent Hypoxia Promoting Atherosclerosis

目的观察间歇低氧时大鼠血管平滑肌屏氧酶1(PON1)和Rho激酶的表达,探讨间歇低氧与动脉粥样硬化(AS)之间关系的分子机制。方法将4组雄性Wistar大鼠分为常氧(A)组、间歇低氧(B)组、间歇低氧+瑞舒伐他汀(C)组和间歇低氧+法舒地尔(D)组,并设立正常对照(E)组,30 d后行血脂、体质量、形态学检测,RT-PCR检测PON1和Rho激酶mRNA表达,并检测PON1和Rho GTPases活性。结果与E组对比,A、B、C、D组大鼠血脂均显著增高,主动脉内膜增生明显,PON1表达水平及活性显著降低,Rho激酶表达及Rho GTPases活性显著增加;与A组对比,B组大鼠血脂无显著差异,主动脉内膜增生显著增加,PON1表达水平及活性显著降低,Rho激酶表达及Rho GTPases活性显著增加;与B组对比,C组大鼠血脂显著降低,D组大鼠血脂无显著差异,但主动脉内膜增生均明显改善,C组PON1表达及活性显著增加,D组PON1表达及活性无显著差异,但C、D组Rho激酶表达及Rho GTPases活性均显著降低,且2组间无差异。结论间歇低氧可促进AS发生,PON1及Rho激酶激活与之密切相关。

Objective To study the expression of paranoxonase-1（PON1） and Rho kinase in vascular smooth muscle with sleep intermittent hypoxia,so as to explore the molecular mechanisms involved in intermittent hypoxia and inflammation induced atherosclerosis.Methods Male Wistar rats were randomly divided into 5 groups：normal oxygen group（A group,breathing 21% O2 for 8 h per day）,intermittent hypoxia group（B group,breathing 10% O2 and air altered per 90 sec for 8 h per day）,rosuvastatin group（C group,breathing 10% O2 and air altered per 90 sec for 8 h per day,20 mg·kg-1·d-1 rosuvastatin Qd,p.o.）,fasudil group（D group,breathing 10% O2 and air altered per 90 sec for 8 h per day,20 mg·kg-1·d-1 fasudil Qd,i.h.） and control group（E group,breathing 21% O2 for 8 h per day）.Thirty days later,lipid,weight,HE staining of aortic endothelium,PON1 and Rho kinase mRNA expression and PON1 and Rho kinase activities were measured respectively.Results The levels of total cholesterol（TC）,triglyceride（TG）,low density lipoprotein cholesterol（LDL-C） were increased,high density lipoprotein cholesterol（HDL-C）,PON1 mRNA expression and activity were decreased and Rho kinase mRNA expression and activity were increased in A,B,C,D group as compared with E group（P 0.05 or P 0.01）.Moreover,HE staining showed that atherosclerotic changes in aorta in A,B,C,D group were increased.The level of lipid in B group were not changed,but atherosclerotic changes in aorta was deteriorated,PON1 mRNA expression and activity were decreased and Rho kinase mRNA expression and activity were increased significantly as compared with A group.In C group,the level of TG and LDL-C were decreased,atherosclerotic changes in aorta were improved,PON1 mRNA expression and activity were increased and Rho kinase mRNA expression and activity were decreased as compared with B group.In D group,lipid and the level of lipid and PON1 mRNA expression and activity were not changed,atherosclerotic changes in aorta were improved and Rho kinase mRNA expression and activity were decreased as compared with B group.Conclusion Intermittent hypoxia was a dangerous factor that associated with the occurrence and development of atherosclerosis.The activations of the structure of high density lipoprotein cholesterol-PON1 and Rho kinase may be the key factors in atherosclerosis under sleep intermittent hypoxia.