瑞舒伐他汀对同型半胱氨酸诱导的小鼠血管平滑肌细胞去分化和内质网应激的影响及其机制研究

doi:10.12047/j.cjap.5489.2018.012

中国应用生理学杂志 ›› 2018, Vol. 34 ›› Issue (1): 43-48.doi: 10.12047/j.cjap.5489.2018.012

瑞舒伐他汀对同型半胱氨酸诱导的小鼠血管平滑肌细胞去分化和内质网应激的影响及其机制研究

周昌钻^1,2, 潘孙雷¹, 林辉¹, 孟立平¹, 季政¹, 池菊芳¹, 郭航远¹

1. 绍兴市人民医院心内科, 浙江绍兴 312000;
2. 温州中西医结合医院, 浙江温州 325000

收稿日期:2016-09-09 修回日期:2017-06-27 出版日期:2018-01-28 发布日期:2018-06-19
通讯作者: 郭航远,Tel:+86-13567200808;E-mail:ghangyuan@outlook.com E-mail:ghangyuan@outlook.com
基金资助:
浙江省省部共建重点项目（WKJ-ZJ-1729）

Effects of rosuvastatin in homocysteine induced mouse vascular smooth muscle cell dedifferentiation and endoplasmic reticulum stress and its mechanisms

ZHOU Chang-zuan^1,2, PAN Sun-lei¹, LIN Hui¹, MENG Li-ping¹, JI Zheng¹, CHI Ju-fang¹, GUO Hang-yuan¹

1. Department of Cardiology, Shaoxing People's Hospital, Shaoxing 312000;
2. Department of Cardiology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine, Wenzhou 32500, China

Received:2016-09-09 Revised:2017-06-27 Online:2018-01-28 Published:2018-06-19
Supported by:
浙江省省部共建重点项目（WKJ-ZJ-1729）

摘要/Abstract

摘要： 目的：探讨瑞舒伐他汀（Rsv）对同型半胱氨酸（Hcy）诱导的小鼠血管平滑肌细胞（VSMCs）去分化及内质网应激（ERS）的影响。方法：Hcy和不同浓度瑞舒伐他汀（0.1，1.0，10 μmol/L）干预VSMCs，48 h后检测细胞骨架及表型蛋白（α-SMA）、钙调节蛋白（calponin）和骨桥蛋白（OPN）变化，并检测ERS相关mRNA （Herpud1，XBP1s和GRP78）在不同时间点的水平；再在Hcy及Rsv干预基础上给予ERS抑制剂4-苯基丁酸（4-PBA）或诱导剂衣霉素来调控细胞ERS水平，检测细胞增殖、迁移和表型蛋白表达，明确ERS在Rsv表型保护中的作用；在Hcy及Rsv干预基础上给予雷帕霉素靶蛋白（mTOR）-P70S6激酶（P70S6K）信号抑制剂雷帕霉素或激活剂磷脂酸，检测mTOR-P70S6K磷酸化和ERS水平，明确mTOR-P70S6通路在Rsv调控ERS中的作用。结果：与Hcy组相比，Hcy+中Rsv组（1 μmol/L）和Hcy+高Rsv组（10 μmol/L）细胞骨架极性明显增强，α-SMA、calponin表达升高，而OPN及ERS相关mRNA水平显著降低（P<0.01）；与Hcy组比较，Hcy+Rsv组和Hcy+4-PBA组增殖、迁移水平降低（P<0.01），收缩蛋白表达增强，但衣霉素干预则逆转了Rsv的上述作用；与Hcy组相比，Hcy+Rsv组和Hcy+雷帕霉素组的mTOR-P70S6K磷酸化及ERS水平降低（P<0.01），但磷脂酸干预抑制了Rsv对mTOR-P70S6K通路和ERS的影响。结论：瑞舒伐他汀可能通过mTOR-P70S6K通路抑制ERS水平，抑制Hcy诱导的小鼠VSMCs去分化改变。

关键词: 表型去分化, 血管平滑肌, 瑞舒伐他汀, 内质网应激, 同型半胱氨酸, 小鼠

Abstract: Objective: To investigate the effect of rosuvastatin on homocysteine (Hcy) induced mousevascular smooth muscle cells(VSMCs) dedifferentiation and endoplasmic reticulum stress(ERS).Methods: VSMCs were co-cultured with Hcy and different concentration of rosuvastatin (0.1, 1.0 and 10 μmol/L). Cytoskeleton remodeling, VSMCs phenotype markers (smooth muscle actin-α, calponin and osteopontin) and ERS marker mRNAs (Herpud1, XBP1s and GRP78) were detected at predicted time. Tunicamycin was used to induce, respectively 4-phenylbutyrate(4-PBA) inhibition, ERS in VSMCs and cellular migration, proliferation and expression of phenotype proteins were analyzed. Mammalian target of rapamycin(mTOR)-P70S6 kinase (P70S6K) signaling agonist phosphatidic acid and inhibitor rapamycin were used in Rsv treated VSMCs. And then mTOR signaling and ERS associated mRNAs were detected.Results: Compared with Hcy group, Hcy+ Rsv group (1.0 and 10 μmol/L) showed enhanced α-SMA and calponin expression (P<0.01), suppressed ERS mRNA levels (P<0.01) and promoted polarity of cytoskeleton. Compared with Hcy group, Hcy+Rsv group and Hcy+4-PBA group showed suppressed proliferation, migration and enhanced contractile protein expression (P<0.01); while tunicamycin could reverse the effect of Rsv on Hcy treated cells. Furthermore, alleviated mTOR-P70S6K phosphorylation and ERS (P<0.01)were observed in Hcy+Rsv group and Hcy+rapamycin group, compared with Hcy group; while phosphatidic acid inhibited the effect of Rsv on mTOR signaling activation and ERS mRNA levels (P<0.01).Conclusion: Rosuvastatin could inhibit Hcy induced VSMCs dedifferentiation via suppressing ERS, which might be regulated by mTOR-P70S6K signaling.

Key words: phenotype dedifferentiation, vascular smooth muscle cell, rosuvastatin, endoplasmic reticulum stress, homocysteine, mouse

周昌钻, 潘孙雷, 林辉, 孟立平, 季政, 池菊芳, 郭航远. 瑞舒伐他汀对同型半胱氨酸诱导的小鼠血管平滑肌细胞去分化和内质网应激的影响及其机制研究[J]. 中国应用生理学杂志, 2018, 34(1): 43-48.

ZHOU Chang-zuan, PAN Sun-lei, LIN Hui, MENG Li-ping, JI Zheng, CHI Ju-fang, GUO Hang-yuan. Effects of rosuvastatin in homocysteine induced mouse vascular smooth muscle cell dedifferentiation and endoplasmic reticulum stress and its mechanisms[J]. CJAP, 2018, 34(1): 43-48.

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瑞舒伐他汀对同型半胱氨酸诱导的小鼠血管平滑肌细胞去分化和内质网应激的影响及其机制研究

Effects of rosuvastatin in homocysteine induced mouse vascular smooth muscle cell dedifferentiation and endoplasmic reticulum stress and its mechanisms

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