期刊
CARDIOVASCULAR RESEARCH
卷 118, 期 5, 页码 1359-1373出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvab171
关键词
NOX5; Hypertension; Oxidative stress; Vascular smooth muscle cells
资金
- British Heart Foundation (BHF) [RG/13/7/30099, RE/18/6/34217]
- Medical Reseach Council (MRC) [MC-PC-15076]
- BHF Chair award [CH/4/29762]
- University of Glasgow Walton Fellowship
- Higher Education Commission (HEC), Pakistan
In this study, the role of NOX-induced oxidative stress in VSMCs in human hypertension was explored, with a focus on NOX5 and its connection to c-Src. The findings suggest that the NOX5/ROS/c-Src pathway plays a significant role in VSMC dysfunction in hypertension, and dampening this pathway may have therapeutic potential in reducing hypertension-associated vascular injury.
Aims NOX-derived reactive oxygen species (ROS) are mediators of signalling pathways implicated in vascular smooth muscle cell (VSMC) dysfunction in hypertension. Among the numerous redox-sensitive kinases important in VSMC regulation is c-Src. However, mechanisms linking NOX/ROS to c-Src are unclear, especially in the context of oxidative stress in hypertension. Here, we investigated the role of NOX-induced oxidative stress in VSMCs in human hypertension focusing on NOX5, and explored c-Src, as a putative intermediate connecting NOX5-ROS to downstream effector targets underlying VSMC dysfunction. Methods and results VSMC from arteries from normotensive (NT) and hypertensive (HT) subjects were studied. NOX1,2,4,5 expression, ROS generation, oxidation/phosphorylation of signalling molecules, and actin polymerization and migration were assessed in the absence and presence of NOX5 (melittin) and Src (PP2) inhibitors. NOX5 and p22phox-dependent NOXs (NOX1-4) were down-regulated using NOX5 siRNA and p22phox-siRNA approaches. As proof of concept in intact vessels, vascular function was assessed by myography in transgenic mice expressing human NOX5 in a VSMC-specific manner. In HT VSMCs, NOX5 was up-regulated, with associated oxidative stress, hyperoxidation (c-Src, peroxiredoxin, DJ-1), and hyperphosphorylation (c-Src, PKC, ERK1/2, MLC20) of signalling molecules. NOX5 siRNA reduced ROS generation in NT and HT subjects. NOX5 siRNA, but not p22phox-siRNA, blunted c-Src phosphorylation in HT VSMCs. NOX5 siRNA reduced phosphorylation of MLC20 and FAK in NT and HT. In p22phox- silenced HT VSMCs, Ang II-induced phosphorylation of MLC20 was increased, effects blocked by melittin and PP2. NOX5 and c-Src inhibition attenuated actin polymerization and migration in HT VSMCs. In NOX5 transgenic mice, vascular hypercontractilty was decreased by melittin and PP2. Conclusion We define NOX5/ROS/c-Src as a novel feedforward signalling network in human VSMCs. Amplification of this system in hypertension contributes to VSMC dysfunction. Dampening the NOX5/ROS/c-Src pathway may ameliorate hypertension-associated vascular injury.
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