Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Section of Neurology, Taichung Veterans General Hospital, Taichung, Taiwan.
Mol Med. 2011 Sep-Oct;17(9-10):1065-74. doi: 10.2119/molmed.2011.00043. Epub 2011 Jun 10.
The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.
BRCA-1 相关蛋白基因 (BRAP) 最近被确定为心肌梗死 (MI) 的易感基因。本研究旨在阐明 BRAP 多态性与颈动脉粥样硬化的关系及其促动脉粥样硬化作用的机制。共有 1749 名中风/心肌梗死患者接受颈动脉超声检查，以测量内膜中层厚度 (IMT) 和斑块。选择启动子多态性 rs11066001 是因为它影响 BRAP 的转录。我们发现，与携带 A 等位基因相比，GG 基因型与至少存在一个斑块的风险增加 1.58 倍有关（P = 0.021）。当根据 IMT 的平均值加 1 个标准差的截断值将受试者进行分组时，在 IMT 较厚的受试者中 GG 基因型的出现频率更高（P = 0.004）。当用脂多糖 (LPS) 处理人主动脉平滑肌细胞 (HASMC) 时，BRAP 的表达显著增加。在用 LPS 处理之前，HASMC 用针对 BRAP 的小干扰 RNA 或乱序序列转染。BRAP 敲低导致 HASMC 增殖减弱，LPS 刺激后单核细胞趋化蛋白-1 (MCP-1) 和白细胞介素-8 (IL-8) 的分泌减少。BRAP 的下调不影响核因子-κB (NF-κB) 的蛋白水平，但阻止其核易位。免疫共沉淀实验证实了 BRAP 与 IKK 信号体的两个主要成分 IκBβ 和 IKKβ 之间的相互作用。总之，BRAP 增加了颈动脉斑块和 IMT 的风险。炎症刺激上调 BRAP 表达，BRAP 通过调节 NF-κB 核易位激活炎症级联反应。
