Caspase-1 Deficiency Decreases Atherosclerosis in Apolipoprotein E-Null Mice
Caspase-1 Deficiency Decreases Atherosclerosis in Apolipoprotein E-Null Mice
复制标题
DOI：
10.1016/j.cjca.2011.10.013
复制
发表时间：
2012-03-01
影响因子：
6.2
通讯作者：
Whitman, Stewart C.
中科院分区：
文献类型：
--
作者：
Gage, Jessica;Hasu, Mirela;Whitman, Stewart C.
背景资料：Caspase-1是一种半胱氨酸蛋白酶，通过蛋白水解激活促炎细胞因子白细胞介素（IL）-1 β和IL-18，促进哺乳动物免疫。确定caspase-1缺陷是否可以保护载脂蛋白E-null（Apoe（-/-））小鼠动脉粥样硬化，性别匹配，配对同窝Apoe（-/-）小鼠（Casp 1（+/+）Apoe（-/-））或无（Casp 1（-/-）Apoe（-/-）），分别饲喂低脂饲料26周或饱和脂肪和胆固醇饲料8周。血浆脂质和脂蛋白进行了测定和动脉粥样硬化定量在主动脉窦和主动脉弓。结果：在任何饮食，caspase-1缺乏症不影响血清总胆固醇浓度和脂蛋白胆固醇分布。然而，caspase-1缺乏显著降低了35%-45%的雄性小鼠的升主动脉粥样硬化。我们进一步检查了动脉粥样硬化病变的2个免疫细胞活化指标：主要组织相容性复合物（MHC）II类和干扰素（IFN）-γ表达。与Casp 1（+/-）Apoe（-/-）小鼠相比，来自两种性别的Casp 1（-/-）Apoe（-/-）小鼠的表达MHC II类的病变相关细胞的数量减少了40%-50%，并且与它们的Casp 1（+/+）Apoe（-/-）对应物相比，雌性Casp 1（-/-）Apoe（-/-）小鼠中的病变相关IFN-γ显著减少。我们的结论是，caspase-1促进动脉粥样硬化通过增强病变的炎症状态，通过一种机制可能涉及激活病变相关的免疫细胞和IFN-γ的表达。
Background: Caspase-1 is a cysteine protease that contributes to mammalian immunity through proteolytic activation of the proinflammatory cytokines, interleukin (IL)-1 beta and IL-18.Methods: To determine if caspase-1 deficiency can protect apolipoprotein E-null (Apoe(-/-)) mice from atherosclerosis, gender-matched, paired-littermate Apoe(-/-) mice with (Casp1(+/+) Apoe(-/-)) or without (Casp1(-/-) Apoe(-/-)) a functional caspase-1 (Casp1) gene were fed either a low fat diet for 26 weeks, or a saturated fat and cholesterolenriched diet for 8 weeks. Plasma lipids and lipoproteins were determined and atherosclerosis was quantified in the aortic sinus and aortic arch.Results: On either diet, caspase-1 deficiency did not affect total serum cholesterol concentrations and lipoprotein-cholesterol distributions. However, caspase-1 deficiency significantly decreased atherosclerosis in the ascending aorta by 35%-45% in both sexes of mice fed either diet. We further examined atherosclerotic lesions for 2 indices of immune cell activation: Major Histocompatibility Complex (MHC) class II and interferon (IFN)-gamma expression. There was a 40%-50% reduction in the number of lesion-associated cells expressing MHC class II from both sexes of Casp1(-/-) Apoe(-/-) mice compared with Casp1(+/-) Apoe(-/-) mice and, a significant reduction in lesion-associated IFN-gamma in female Casp1(-/-) Apoe(-/-) compared with their Casp1(+/+) Apoe(-/-) counterparts.Conclusions: We conclude that caspase-1 promotes atherosclerosis by enhancing the inflammatory status of the lesion through a mechanism likely involving activation of lesion-associated immune cells and IFN-gamma expression.