Rapamycin attenuates endothelial apoptosis induced by low shear stress via mTOR and sestrin1 related redox regulation.
Rapamycin attenuates endothelial apoptosis induced by low shear stress via mTOR and sestrin1 related redox regulation.
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雷帕霉素通过 mTOR 和 Sestrin1 相关氧化还原调节减弱低剪切应力诱导的内皮细胞凋亡
DOI：
10.1155/2014/769608
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发表时间：
2014
影响因子：
4.6
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Zhang J;Wang Z;Zhang J;Zuo G;Li B;Mao W;Chen S
背景研究表明，冠状动脉的雷帕霉素洗脱支架（RES）段内的剪切应力（SS）显著降低。雷帕霉素在SS变低的支架动脉内皮化中的作用仍不清楚。由于mTOR（mammalian target of rapamycin）通路参与了抗氧化sestrins的表达，我们推测雷帕霉素通过mTOR和sestrin1相关的氧化还原调节减弱低SS（low SS，LSS）诱导的内皮功能障碍。方法和结果。为了模拟LSS对支架动脉的作用，使用平行板流动室观察LSS和雷帕霉素对内皮细胞（EC）的相互作用。结果表明，LSS可显著诱导EC凋亡，雷帕霉素预处理可减轻LSS诱导的EC凋亡。雷帕霉素通过抑制sestrin 1的下调而减弱LSS诱导的活性氧（ROS）和活性氮（RNS）的产生。mTORC1和mTORC2的活性被LSS矛盾地调节。通过靶向小干扰RNA（siRNA）转染抑制rictor表达可抑制LSS诱导的sestrin 1下调，但抑制raptor则不然。结论.雷帕霉素可能通过靶向mTORC 2抑制sestrin 1下调，从而抑制LSS诱导的EC氧化凋亡。我们的研究结果提供了体外证据来解释RES支架动脉的病理生理学。
Background. Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation. Methods and Results. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not. Conclusions. Rapamycin may prohibit sestrin1 downregulation through targeting mTORC2 in appeasing LSS induced EC oxidative apoptosis. Our results provide the in vitro evidence to explain the pathophysiology of RES stented arteries.
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影响因子：
11.3
作者：
Papafaklis, Michail I.;Bourantas, Christos V.;Michalis, Lampros K.
通讯作者：
Michalis, Lampros K.
DOI：
10.1126/science.1182228
发表时间：
2010-03-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lee JH;Budanov AV;Park EJ;Birse R;Kim TE;Perkins GA;Ocorr K;Ellisman MH;Bodmer R;Bier E;Karin M
通讯作者：
Karin M
DOI：
10.18632/aging.100182
发表时间：
2010-08
期刊：
Aging
影响因子：
--
作者：
Pani G
通讯作者：
Pani G
影响因子：
11.1
作者：
Budanou, Andrei V.;Lee, Jun Hee;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
3.1
作者：
Chen, Shao-Liang;Hu, Zuo-Ying;Chen, Mengxuan
通讯作者：
Chen, Mengxuan