Song Wei, Yang Zhen, He Ben
Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Hypertension and Vascular Disease, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
PLoS One. 2014 Oct 20;9(10):e111093. doi: 10.1371/journal.pone.0111093. eCollection 2014.
Increasing evidences have suggested vascular endothelial inflammatory processes are the initiator of atherosclerosis. Bestrophin 3 (Best-3) is involved in the regulation of cell proliferation, apoptosis and differentiation of a variety of physiological functions, but its function in cardiovascular system remains unclear. In this study, we investigated the effect of Best-3 on endothelial inflammation. We first demonstrated that Best-3 is expressed in endothelial cells and decreased after tumor necrosis factor-α (TNFα) challenge. Overexpression of Best-3 significantly attenuated TNFα-induced expression of adhesion molecules and chemokines, and subsequently inhibited the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of Best-3 with siRNA resulted in an enhancement on TNFα-induced expression of adhesion molecules and chemokines and adhesion of monocytes to HUVECs. Furthermore, overexpression of Best-3 with adenovirus dramatically ameliorated inflammatory response in TNFα-injected mice. Mechanistically, we found up-regulation of Best-3 inhibited TNFα-induced IKKβ and IκBα phosphorylation, IκBα degradation and NF-κB translocation. Our results demonstrated that Best-3 is an endogenous inhibitor of NF-κB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases.
越来越多的证据表明，血管内皮炎症过程是动脉粥样硬化的起始因素。Bestrophin 3（Best-3）参与多种生理功能的细胞增殖、凋亡和分化调节，但其在心血管系统中的功能仍不清楚。在本研究中，我们调查了Best-3对内皮炎症的影响。我们首先证明Best-3在内皮细胞中表达，且在肿瘤坏死因子-α（TNFα）刺激后降低。Best-3的过表达显著减弱了TNFα诱导的黏附分子和趋化因子的表达，并随后抑制了单核细胞与人脐静脉内皮细胞（HUVECs）的黏附。相反，用小干扰RNA（siRNA）敲低Best-3导致TNFα诱导的黏附分子和趋化因子表达以及单核细胞与HUVECs黏附增强。此外，用腺病毒过表达Best-3显著改善了TNFα注射小鼠的炎症反应。机制上，我们发现Best-3的上调抑制了TNFα诱导的IKKβ和IκBα磷酸化、IκBα降解以及NF-κB易位。我们的结果表明Best-3是内皮细胞中NF-κB信号通路的内源性抑制剂，提示强制表达Best-3可能是治疗血管炎性疾病的一种新方法。
