Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.
Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.
复制标题
甲硫氨酸亚砜还原酶 A 的肝脏过度表达可减少载脂蛋白 E 缺陷小鼠的动脉粥样硬化。
DOI：
10.1194/jlr.m058776
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发表时间：
2015-10
影响因子：
6.5
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Xu YY;Du F;Meng B;Xie GH;Cao J;Fan D;Yu H
甲硫氨酸亚砜还原酶A（Methylethanesulfonate reductase A，MsrA）是一种将蛋氨酸-S-亚砜转化为甲硫氨酸的特异性酶，在调节蛋白质功能和维持氧化还原稳态中起重要作用。在这项研究中，我们研究了肝脏MsrA过表达对载脂蛋白E缺陷（apoE-/-）小鼠脂质代谢和动脉粥样硬化的影响。体外研究表明，慢病毒介导的人MsrA（hMsrA）过表达可上调HepG 2细胞中肝X受体α、清道夫受体B类I型和ABCA 1等几个关键脂蛋白代谢相关基因的表达水平。ApoE−/−小鼠静脉注射慢病毒，以实现主要在肝脏中的高水平hMsrA表达。我们发现，肝脏hMsrA表达显著降低血浆VLDL/LDL水平，提高血浆超氧化物歧化酶和对氧磷酶-1活性，并降低apoE−/−小鼠的血浆血清淀粉样蛋白A水平，通过显著改变肝脏中涉及胆固醇选择性摄取，转化和排泄到胆汁，TG生物合成和炎症的几个基因的表达。此外，过表达hMsrA导致肝脂肪变性和主动脉粥样硬化减少。这些结果表明，肝脏MsrA可能是一个有效的治疗靶点，改善血脂异常，减少动脉粥样硬化相关的心血管疾病。
Methionine sulfoxide reductase A (MsrA), a specific enzyme that converts methionine-S-sulfoxide to methionine, plays an important role in the regulation of protein function and the maintenance of redox homeostasis. In this study, we examined the impact of hepatic MsrA overexpression on lipid metabolism and atherosclerosis in apoE-deficient (apoE−/−) mice. In vitro study showed that in HepG2 cells, lentivirus-mediated human MsrA (hMsrA) overexpression upregulated the expression levels of several key lipoprotein-metabolism-related genes such as liver X receptor α, scavenger receptor class B type I, and ABCA1. ApoE−/− mice were intravenously injected with lentivirus to achieve high-level hMsrA expression predominantly in the liver. We found that hepatic hMsrA expression significantly reduced plasma VLDL/LDL levels, improved plasma superoxide dismutase, and paraoxonase-1 activities, and decreased plasma serum amyloid A level in apoE−/− mice fed a Western diet, by significantly altering the expression of several genes in the liver involving cholesterol selective uptake, conversion and excretion into bile, TG biosynthesis, and inflammation. Moreover, overexpression of hMsrA resulted in reduced hepatic steatosis and aortic atherosclerosis. These results suggest that hepatic MsrA may be an effective therapeutic target for ameliorating dyslipidemia and reducing atherosclerosis-related cardiovascular diseases.