Department of Combat Casualty Care Training, Medical Service Training Base, Third Military Medical University, Chongqing, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Life Sci. 2019 Jan 1;216:59-66. doi: 10.1016/j.lfs.2018.11.019. Epub 2018 Nov 9.
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.
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 AngII-induced 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.
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.
我们之前报道过血管紧张素 II（AngII）可恢复失血性休克引起的血管反应性降低。在这项研究中，我们研究了 AngII 的有益作用是否与缝隙连接（GJ）和连接蛋白 43（Cx43）的调节有关，以及 MAPK 信号和 microRNA（miR-1）在这个过程中的意义。
我们的结果表明，在失血性休克或缺氧后，GJ 阻断或 Cx43 敲低抑制了血管紧张素 II 诱导的肠系膜上动脉血管反应性增加和血管平滑肌细胞（VSMC）的收缩反应。AngII 处理可增加 Cx43 的表达和丝氨酸 262 磷酸化，并在缺氧后恢复 VSMC 之间的 GJIC。ERK-siRNA 转导的细胞中 AngII 诱导的 Cx43 表达和磷酸化上调被阻断，但 p38-siRNA 转导的细胞中没有被阻断。缺氧后 miR-1 水平升高；AngII 处理可逆转 miR-1 的上调，而 ERK-siRNA 则消除了 AngII 的这种作用。在缺氧细胞中，将 miR-1 模拟物转染到 VSMC 中可降低 Cx43 的表达和 VSMC 反应性，而 miR-1 抑制剂则可增加两者。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。
AngII 通过恢复 VSMC 中 Cx43 的表达和磷酸化及其介导的 GJIC，为血管功能提供保护。ERK 介导 AngII 诱导的 Cx43 丝氨酸 262 磷酸化。此外，miR-1 也参与了这一过程，AngII 可能通过 ERK 信号部分抑制 miR-1 升高来发挥其保护作用。
