A Novel STAT3-Mediated GATA6 Pathway Contributes to tert-Butylhydroquinone- (tBHQ-) Protected TNFα-Activated Vascular Cell Adhesion Molecule 1 (VCAM-1) in Vascular Endothelium

• Published in: Oxidative medicine and cellular longevity 2020, Vol.2020 (2020), p.1-17
• Main Authors: Li, Songtao, Dou, Xiaobing, Qian, Qianyu, Fu, Ai, Zhao, Xindi, Xu, Tiantian, Wei, Haibin, Ning, Hua, Zhou, Li, Yang, Zhen
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Atherosclerosis; Autophagy; Cardiovascular disease; Cell adhesion & migration; Coronary vessels; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Food; GATA6 Transcription Factor - metabolism; Gene expression; Hydroquinones - pharmacology; Laboratory animals; Male; Mice; Oxidative stress; Proteins; Reagents; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Transcription factors; Tumor Necrosis Factor-alpha - metabolism; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1942-0900; 1942-0994
• DOI: 10.1155/2020/6584059

The activation of vascular cell adhesion molecule 1 (VCAM-1) in vascular endothelial cells has been well considered implicating in the initiation and processing of atherosclerosis. Oxidative stress is mechanistically involved in proatherosclerotic cytokine-induced VCAM-1 activation. tert-Butylhydroquinone (tBHQ), a synthetic phenolic antioxidant used for preventing lipid peroxidation of food, possesses strongly antioxidant capacity against oxidative stress-induced dysfunction in various pathological process. Here, we investigated the protective role of tBHQ on tumor necrosis factor alpha- (TNFα-) induced VCAM-1 activation in both aortic endothelium of mice and cultured human vascular endothelial cells and uncovered its potential mechanisms. Our data showed that tBHQ treatment significantly reversed TNFα-induced activation of VCAM-1 at both transcriptional and protein levels. The mechanistic study revealed that inhibiting neither nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nor autophagy blocked the beneficial role of tBHQ. Alternatively, tBHQ intervention markedly alleviated TNFα-increased GATA-binding protein 6 (GATA6) mRNA and protein expressions and its translocation into nucleus. Further investigation indicated that tBHQ-inhibited signal transducer and activator of transcription 3 (STAT3) but not mitogen-activated protein kinase (MAPK) pathway contributed to its protective role against VCAM-1 activation via regulating GATA6. Collectively, our data demonstrated that tBHQ prevented TNFα-activated VCAM-1 via a novel STAT3/GATA6-involved pathway. tBHQ could be a potential candidate for the prevention of proatherosclerotic cytokine-caused inflammatory response and further dysfunctions in vascular endothelium.