ERK and miRNA-1 target Cx43 expression and phosphorylation to modulate the vascular protective effect of angiotensin II
ERK and miRNA-1 target Cx43 expression and phosphorylation to modulate the vascular protective effect of angiotensin II
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ERK 和 miRNA-1 靶向 Cx43 表达和磷酸化来调节血管紧张素 II 的血管保护作用
DOI：
10.1016/j.lfs.2018.11.019
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发表时间：
2019-01-01
期刊：
影响因子：
6.1
通讯作者：
Yang, Guangming
中科院分区：
文献类型：
--
作者：
Lei, Yan;Peng, Xiaoyong;Yang, Guangming
目的和方法：我们以前报道，血管紧张素II（AngII）恢复血管反应性减少失血性休克。在这项研究中，我们研究了AngII的有益作用是否与间隙连接（GJs）和连接蛋白43（Cx43）的调节有关，以及MAPK信号传导和microRNA（miR-1）在这一过程中的意义。我们的研究结果表明，在失血性休克或缺氧后，GJs的阻断或Cx43的敲低抑制了AngII-诱导的上级肠系膜动脉的血管反应性和血管平滑肌细胞（VSMCs）的收缩反应的增加。血管紧张素II治疗增加Cx43的表达和Ser 262的磷酸化，并恢复缺氧后VSMCs之间的间隙连接通讯（GJIC）。AngII诱导的Cx43表达和磷酸化的上调在用ERK-siRNA转导的细胞中被阻断，但在用p38-siRNA转导的细胞中不被阻断。miR-1水平在缺氧后升高; AngII处理逆转miR-1的上调，而ERK-siRNA消除AngII的作用。在缺氧细胞中，miR-1模拟物转染到VSMC中降低Cx43表达和VSMC反应性，而miR-1抑制剂增加两者。同样在缺氧细胞中，miR-1消除了AngII对Cx43表达和VSMC反应性的恢复作用。意义：AngII通过恢复VSMC中Cx43及其介导的GJIC的表达和磷酸化来保护血管功能。ERK介导AngII诱导的Cx43在Ser 262的磷酸化。此外，miR-1参与了这一过程，AngII可能通过ERK信号抑制miR-1升高而部分发挥其保护作用。
Aims and methods: We previously reported that angiotensin II (AngII) restores the vascular reactivity diminished by hemorrhagic shock. In this study, we investigated whether the beneficial effects of AngII are related to regulation of gap junctions (GJs) and connexin43 (Cx43), and the implication of MAPK signaling and microRNA (miR-1) in this process.Key findings: Our results show that after hemorrhagic shock or hypoxia, the blockade of GJs or knockdown of Cx43 inhibits the AngII-induced increase in vascular reactivity of superior mesenteric arteries and the contractile response of vascular smooth muscle cells (VSMCs). AngII treatment increases Cx43 expression and phosphorylation at Ser262, and restores gap-junctional communication (GJIC) between VSMCs after hypoxia. The AngIIinduced up-regulation of Cx43 expression and phosphorylation is blocked in cells transduced with ERK-siRNA, but is not blocked in cells transduced with p38-siRNA. miR-1 levels are elevated after hypoxia; AngII treatment reverses the up-regulation of miR-1, while ERK-siRNA abolishes that effect of AngII. In hypoxic cells, transfection of a miR-1 mimic into VSMCs decreases Cx43 expression and VSMC reactivity, whereas a miR-1 inhibitor increases both. Also in hypoxic cells, miR-1 eliminates the restoration effects of AngII on Cx43 expression and VSMC reactivity.Significance: AngII provides protection of vascular function through the restoration of the expression and phosphorylation of Cx43 and its mediated GJIC in VSMCs. It is ERK that mediates the AngII-induced phosphorylation of Cx43 at Ser262. Additionally, miR-1 is involved in this process, and AngII may exert its protective effect partially by inhibiting miR-1 elevation via ERK signaling.