HSP22在高脂致动脉粥样硬化病变中的作用及对他汀干预的影响

Role of HSP22 in atherosclerosis induced by high-fat diet and effects of statin

目的:研究热休克蛋白22(heat shock protein 22,HSP22)在高脂饮食诱导的小鼠动脉粥样硬化(atherosclerosis,AS)病变中的作用,及其对阿托伐他汀(atorvastatin,Ator)干预的影响。方法:8~9周龄Apo E^(-/-)和HSP22^(-/-)Apo E^(-/-)和HSP22+Apo E^(-/-)雄性小鼠各18只,每种小鼠分为2个亚组,分别为对照组与他汀干预组(Ator组),HSP22^(-/-)组(KO组)与HSP22^(-/-)他汀干预组(KO+Ator组)及HSP22^+组(Tg组)与HSP22^+他汀干预组(Tg+Ator组),各干预组从第5周开始给予Ator(10 mg·kg^(-1)·d^(-1))干预,各对照组给予等量生理盐水,共饲养13周。采用油红O及苏木精-伊红(hematoxylin-eosin,HE)染色法观察AS病变程度,免疫组化法、Western blot法和ELISA法检测主动脉和血清中HSP22、NF-κB、eNOS、ICAM-1及IL-6的表达。结果:油红O及HE染色示Tg组主动脉斑块相对面积低于KO组(P<0.05)。KO组的血清和主动脉中HSP22的蛋白表达显著低于对照组和Tg组,对照组显著低于Tg组。Tg组及对照组的主动脉eNOS蛋白的表达显著高于KO组。对照组的主动脉NF-κB及ICAM-1蛋白表达较KO组显著降低,较Tg组显著升高。对照组、KO组及Tg组血清IL-6水平的差异无统计学显著性。结论:HSP22基因缺失可上调NF-κB和ICAM-1的表达,降低eNOS的表达,加速AS的进展;HSP22基因过表达可降低NF-κB和ICAM-1的表达,从而改善AS。HSP22基因缺失部分限制了他汀下调NF-κB和ICAM-1及上调eNOS表达的作用;其过表达可促进他汀下调ICAM-1表达,进一步改善AS。

AIM： To evaluate the role of heat shock protein 22（ HSP22） in atherosclerosis（ AS） induced by high-fat diet and in the intervention with atorvastatin（ Ator）. METHODS： Total 3 groups of 8 ^ 9-week-old ApoE^（-/-）,HSP22^（-/-） ApoE^（-/-） and HSP22＋ApoE^（-/-） male mice were used,with 18 mice in each group. After 1 week of adaptive feeding,the mice in each group were randomly divided into 2 subgroups： control group,and Ator group,HSP22 knockout group（ KO group） and HSP22 knockout with Ator treatment group（ KO ＋ Ator group）,and HSP22 overexpression group（ Tg group） and HSP22 overexpression with Ator treatment group（ Tg ＋ Ator group）. Atro at 10 mg· kg^（-1）-d^（-1） was administered to the mice in all Ator groups from the 5 th week. The mice in the control groups were given saline. All these mice were fed for 13 weeks. Oil red O staining and HE staining of the aortic wall of the mice were used to measure the atherosclerotic lesion burdens. The protein levels of HSP22,NF-κB,e NOS,ICAM-1 and IL-6 in the aorta and serum were examined by Western blot,immunohistochemistry and ELISA. RESULTS： Aortic Oil red O staining and HE staining showed that the relative area of aorta plaque in Tg group was less than that in KO group（ P〈0. 05）. The protein expression of HSP22 in Tg group was significantly higher than that in control group and KO group,and its expression in control group was significantly higher than that in KO group. The protein expression of eNOS in Tg group and control group was significantly higher than that in KO group. The protein expression of NF-κB and ICAM-1 in control group was significantly decreased as compared with KO group,and their expression was significantly higher than that in Tg group. No difference of serum IL-6 level was found among Tg group,KO group and control group. CONCLUSION： HSP22 gene deletion up-regulates the expression of NF-κB and ICAM-1,and down-regulates the expression of eNOS,leading to accelerating AS. HSP22 overexpression decreases the expression of NF-κB and ICAM-1 and increases the expression of eNOS,thus attenuating AS development.HSP22 gene deletion partially limits the role of Ator in the expression of NF-κB,ICAM-1 and eNOS. HSP22 overexpression amplifies the reduced expression of ICAM-1 by the intervention with Ator,and further attenuates AS development.