Luo Jun-Yi, Li Xiao-Mei, Zhou Yun, Zhao Qiang, Chen Bang-Dang, Liu Fen, Chen Xiao-Cui, Zheng Hong, Ma Yi-Tong, Gao Xiao-Ming, Yang Yi-Ning
Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Xinjiang Key Laboratory of Cardiovascular Research, Urumqi, Xinjiang, China.
J Mol Cell Cardiol. 2017 Feb;103:56-64. doi: 10.1016/j.yjmcc.2017.01.005. Epub 2017 Jan 12.
Nuclear factor κappa B (NF-κB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to HO-induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under HO-stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-κB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under HO-stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-κB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism.
核因子κB（NF-κB）是冠状动脉疾病（CAD）发生和发展过程中的一种重要转录因子。最近的证据表明，NFKB1基因启动子中的-94 ATTG插入/缺失突变体是一种重要的功能突变体。本研究表明，CAD患者中缺失/缺失（DD）基因型和缺失（D）等位基因的频率显著高于对照组。与携带插入/插入（II）或插入/缺失（ID）基因型的患者相比，携带突变DD基因型的CAD患者病变冠状动脉的狭窄情况更严重。DD基因型CAD患者的血浆内皮型一氧化氮合酶（eNOS）水平较低，而炎性细胞因子白细胞介素-6（IL-6）水平较高，与II或ID基因型患者相比差异均有统计学意义（均P<0.05）。体外研究表明，突变的人脐静脉内皮细胞（DD基因型HUVECs）对过氧化氢（HO）诱导的细胞凋亡更敏感，同时伴有Bcl-2表达降低。此外，在HO刺激下，突变的HUVECs的eNOS mRNA水平较低，但IL-6 mRNA水平较高，且eNOS的磷酸化水平降低（均P<0.05）。与野生型细胞（II基因型）相比，在有或无氧化应激的情况下，突变的HUVECs中总NF-κB p50亚基的蛋白表达均显著下调，并且在HO刺激下，与野生型细胞相比，突变的HUVECs中细胞核p50表达较低，同时p50核转位减少（均P<0.05）。总之，NFKB1基因的突变DD基因型与CAD的风险和严重程度相关。NF-κB p50亚基的下调导致内皮功能障碍和细胞凋亡加剧以及炎症反应增强，这可能是潜在的发病机制。
