Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
Department of Endocrinology and Metabolism, General Hospital of Tianjin Medical University, Tianjin 300052, People's Republic of China.
Thromb Res. 2016 Apr;140:51-58. doi: 10.1016/j.thromres.2016.02.012. Epub 2016 Feb 12.
This study investigated the molecular mechanisms underlying the inhibition of MMP-9 expression by probucol, which is widely used for atherosclerotic prevention, in cultured human umbilical vein endothelial cells (HUVECs) and apoE knockout mice.
We used three target scan algorithms and observed that microRNA (miR)-497 targeted MEK1, a member of the MAPK/ERK signaling involved in regulating MMP-9 expression. HUVECs were treated with TNFα, and apoE knockout mice were fed a high-fat/high-cholesterol diet with or without probucol pretreatment. We focused on the association between miR-497 and MAPK/ERK signaling and MMP-9 expression.
First, miR-497 expression was significantly higher in the probucol-treated HUVECs and apoE knockout mice compared with non-probucol-treated HUVECs and apoE knockout mice (both p<0.05). Second, MAPK/ERK signaling and MMP-9 levels were downregulated in probucol-treated HUVECs that were treated with TNFα (p<0.01), while MAPK/ERK signaling and MMP-9 levels were upregulated after suppression of miR-497 (p<0.01). Third, probucol increased miR-497 expression levels in the aortas of apoE knockout mice (p<0.05) while decreasing the levels of serum lipids and plaque areas (p<0.05), which decreased the MAPK/ERK signaling and MMP-9 levels (p<0.05).
Probucol inhibits MMP-9 expression through regulating miR-497 in HUVECs and apoE knockout mice.
本研究旨在探讨普罗布考（一种广泛用于动脉粥样硬化预防的药物）抑制 MMP-9 表达的分子机制，该机制在培养的人脐静脉内皮细胞（HUVEC）和载脂蛋白 E 敲除（apoE KO）小鼠中起作用。
我们使用了三种靶向扫描算法，观察到 microRNA（miR）-497 靶向 MEK1，MEK1 是 MAPK/ERK 信号通路的一个成员，该信号通路参与调节 MMP-9 的表达。用 TNFα 处理 HUVEC，并用高脂高胆固醇饮食喂养 apoE KO 小鼠，并用或不用普罗布考预处理。我们重点关注 miR-497 与 MAPK/ERK 信号通路和 MMP-9 表达之间的关系。
首先，与未用普罗布考处理的 HUVEC 和 apoE KO 小鼠相比，用普罗布考处理的 HUVEC 和 apoE KO 小鼠的 miR-497 表达显著增加（均 p<0.05）。其次，在用 TNFα 处理的普罗布考处理的 HUVEC 中，MAPK/ERK 信号通路和 MMP-9 水平下调（p<0.01），而抑制 miR-497 后，MAPK/ERK 信号通路和 MMP-9 水平上调（p<0.01）。第三，普罗布考增加了 apoE KO 小鼠主动脉中的 miR-497 表达水平（p<0.05），同时降低了血清脂质和斑块面积（p<0.05），从而降低了 MAPK/ERK 信号通路和 MMP-9 水平（p<0.05）。
普罗布考通过调节 HUVEC 和 apoE KO 小鼠中的 miR-497 抑制 MMP-9 表达。
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