C/EBPβ-PKCε-ERK1/2信号通路在先天性心脏病相关性肺动脉高压中的作用及机制研究

Congenital heart disease-related pulmonary hypertension (PAH) is the most common type of PAH in China. Pulmonary vascular remodeling is the central link in the development of PAH, but the molecular mechanism is not fully elucidated. Sequencing results showed that the expression of protein kinase C epsilon (PKCε) increased. In vitro, the inhibition of PKCε and hypoxia treatment reduced cell proliferation. The phosphorylation level of ERK1/2 was decreased after interfering with PKCε. However, after treatment with ERK1/2 inhibitor, the expression of PKCε was not affected. After administration of PKCε agonist, the phosphorylation level of ERK1/2 was increased. It is suggested that PKCε may induce abnormal proliferation of pulmonary artery smooth muscle cells by regulating ERK1/2 phosphorylation. Bioinformatics results showed that transcription factor C/EBPbeta had binding sites in the promoter region of PKCε. Overexpression of C/EBPbeta increased PKCε transcription and cell proliferation. Therefore, we speculated that the up-regulation of transcription factor C/EBPbeta may lead to the over-activation of PKCε and the increase of ERK1/2 phosphorylation, resulting in the over-proliferation of pulmonary artery smooth muscle cells and the occurrence of pulmonary vascular remodeling. We intend to elucidate the mechanism of pulmonary vascular remodeling in PAH, so as to provide novel targets for clinical prevention and treatment of PAH.

先天性心脏病相关的肺动脉高压（PAH）是我国PAH中最常见类型。肺血管重构是PAH发生发展的中心环节，但分子机制未完全阐明。前期测序结果显示蛋白激酶Cε（PKCε）表达增加。细胞模型中干扰PKCε和低氧处理后，细胞增殖减少。干扰PKCε后，ERK1/2磷酸化水平减少。而ERK1/2抑制剂处理后，PKCε表达无影响。给予PKCε激动剂后，ERK1/2磷酸化水平上调。提示，PKCε可能通过调控ERK1/2磷酸化导致肺动脉平滑肌细胞异常增殖。生物信息学结果显示转录因子C/EBPβ在PKCε启动子区存在结合位点，过表达C/EBPβ可增加PKCε转录和细胞增殖。故推测：在致PAH因素作用下，转录因子C/EBPβ表达上调，导致PKCε过度激活，进而ERK1/2磷酸化增加，导致肺动脉平滑肌细胞过度增殖及肺血管重构的发生。我们拟深入阐明PAH中肺血管重构机制，从而为临床防治PAH提供新的干预靶点。

发现环境化学物暴露致心血管疾病发病风险增加，发现行为方式能够影响心血管疾病发生风险。首先发现了异戊醛与心血管疾病发生率呈正相关。在完全调整的模型中，异戊醛浓度每增加一个单位（ng/mL），甘油三酯增加25.0 mg/dL，白细胞计数增加0.9×10^9/L。这些结果证据表明，异戊醛可能通过升高甘油三酯和白细胞计数来增加心血管疾病的风险。接着，发现血液金属混合物与全因死亡率、心血管死亡率和癌症死亡率相关，镉的贡献程度最大。然后，我们发现尿镉与心血管疾病总风险和个体风险的增加显著相关。一个尿镉浓度单位（Log10）增加与降低0.93 mg/dL高密度脂蛋白胆固醇、增加1.34mg/dL低密度脂蛋白胆固醇和增加1.30mg/dL总胆固醇有关。中介分析显示，高密度脂蛋白胆固醇介导了尿镉与心血管疾病发病风险的关联相关性的4.91%。在生活方式层面，发现65种代谢产物与多变量调整后的冠心病事件显著相关。将这些代谢产物添加到经典的风险预测模型中，提高了评估的冠心病预测准确性。此外，母亲吸烟和非母乳喂养的高血压风险分别高于母亲不吸烟和母乳喂养。母亲吸烟或哺乳与遗传因素在高血压发病率上存在显著的加性相互作用。母亲吸烟和非母乳喂养与成年期高血压风险较高相关，并可能降低与遗传因素相关的高血压风险。最后，发现夜班工人的高血压风险高于白班工人，并且随着夜班工作频率的增加而增加。高血压多基因风险评分较高的长期夜班工人比低多基因风险评分的白班工人患高血压的风险更高。