Yan Lei1, Xiaoyong Peng2, Tao Li2, Liangming Liu2, Guangming Yang3. 1. Department of Combat Casualty Care Training, Medical Service Training Base, Third Military Medical University, Chongqing, China. 2. 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. 3. 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. Electronic address: yanggm971@163.com.
Abstract
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 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. 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.
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 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. 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.
Authors: Yan Lei; Xiaoyong Peng; Yi Hu; Mingying Xue; Tao Li; Liangming Liu; Guangming Yang Journal: Oxid Med Cell Longev Date: 2020-12-03 Impact factor: 6.543
Authors: Akshata A Almad; Arens Taga; Jessica Joseph; Sarah K Gross; Connor Welsh; Aneesh Patankar; Jean-Philippe Richard; Khalil Rust; Aayush Pokharel; Caroline Plott; Mauricio Lillo; Raha Dastgheyb; Kevin Eggan; Norman Haughey; Jorge E Contreras; Nicholas J Maragakis Journal: Proc Natl Acad Sci U S A Date: 2022-03-21 Impact factor: 12.779