Ivabradine Prevents Low Shear Stress Induced Endothelial Inflammation and Oxidative Stress via mTOR/eNOS Pathway.
Ivabradine Prevents Low Shear Stress Induced Endothelial Inflammation and Oxidative Stress via mTOR/eNOS Pathway.
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伊伐布雷定通过 mTOR/eNOS 通路预防低剪切应力诱导的内皮炎症和氧化应激
DOI：
10.1371/journal.pone.0149694
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Li B;Zhang J;Wang Z;Chen S
伊伐布雷定不仅降低心率，还具有其他心脏和血管保护作用，包括抗炎和抗氧化。由于内皮型一氧化氮合酶（eNOS）是维持内皮活性的关键酶，我们旨在研究伊伐布雷定对低切应力（LSS）诱导的炎症和内皮损伤的影响以及eNOS在其中的作用。内皮细胞（EC）以2dyne/cm 2经受LSS，并接受伊伐布雷定（0.04μM）或LY 294002（10μM）预处理1小时。定量PCR检测IL-6、VCAM-1沿着及eNOS mRNA表达。用二氢乙锭（DHE）和DCF法检测细胞内活性氧（ROS）水平，用Western blot法检测细胞内蛋白磷酸化水平。这表明伊伐布雷定可降低LSS诱导的内皮细胞炎症和氧化应激。Western blot显示rictor和Akt-Ser 473的磷酸化水平降低，eNOS-Thr 495的磷酸化水平升高。然而，mTORC 1通路仅在30分钟内施加LSS时增加。伊伐布雷定可逆转这些效应。伊伐布雷定似乎通过激发mTORC 2/Akt磷酸化和抑制mTORC 1诱导的eNOS-Thr 495活化来减少ROS生成。这些结果共同表明，伊伐布雷定通过mTORC 2/Akt激活和mTORC 1/eNOS减少抑制LSS诱导的内皮炎症和氧化应激。
Ivabradine not only reduces heart rate but has other cardiac and vascular protective effects including anti-inflammation and anti-oxidation. Since endothelial nitric oxide synthase (eNOS) is a crucial enzyme in maintaining endothelial activity, we aimed to investigate the impact of ivabradine in low shear stress (LSS) induced inflammation and endothelial injury and the role of eNOS played in it. Endothelial cells (ECs) were subjected to LSS at 2dyne/cm2, with 1 hour of ivabradine (0.04μM) or LY294002 (10μM) pre-treatment. The mRNA expression of IL-6, VCAM-1 along with eNOS were measured by QPCR. Reactive oxygen species (ROS) was detected by dihydroethidium (DHE) and DCF, and protein phosphorylation was detected by western blot. It demonstrated that ivabradine decreased LSS induced inflammation and oxidative stress in endothelial cells. Western blot showed reduced rictor and Akt-Ser473 as well as increased eNOS-Thr495 phosphorylation. However, mTORC1 pathway was only increased when LSS applied within 30 minutes. These effects were reversed by ivabradine. It would appear that ivabradine diminish ROS generation by provoking mTORC2/Akt phosphorylation and repressing mTORC1 induced eNOS-Thr495 activation. These results together suggest that LSS induced endothelial inflammation and oxidative stress are suppressed by ivabradine via mTORC2/Akt activation and mTORC1/eNOS reduction.