Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Oxid Med Cell Longev. 2022 Oct 22;2022:9494926. doi: 10.1155/2022/9494926. eCollection 2022.
Endothelial apoptosis is the core pathological change in atherosclerotic cardiovascular disease, including coronary artery disease (CAD). Determining the molecular mechanisms underlying endothelial apoptosis is important. Nuclear factor kappa B (NF-B) is a crucial transcription factor for controlling apoptosis. Our previous study demonstrated that the -94 ATTG ins/del mutant in the promoter of gene (rs28362491) is a risk factor for CAD. In the present study, we found that rs28362491 polymorphism was positively associated with increased major adverse cardiac and cerebrovascular events (MACCEs) in CAD patients. After adjusting for confounding factors including age, smoking, hypertension, glucose, and low-density lipoprotein cholesterol, the mutant DD genotype was an independent predictor of MACCEs (OR = 2.578, 95%CI = 1.64-4.05, = 0.003). The study showed that mutant human umbilical vein endothelial cells (DD-mutant HUVECs) were more susceptible to high-glucose/palmitate-induced apoptosis, which was accompanied by decreased p50 expression and increased expression of cleaved caspase-3, Cytochrome c, and phospho-p65 ( < 0.05). The mitochondrial membrane potential was significantly lower, while increasing levels of mtROS and more opening of the mPTP were observed in DD-mutant HUVECs ( < 0.05). Furthermore, the percentage of cells with fragmented or spherical mitochondria was significantly higher in DD-mutant HUVECs than in wild-type cells (genotype II HUVECs) ( < 0.05). In addition, after stimulation with high glucose/palmitate, the gene mutant significantly increased the expression of Drp1, which indicated that the gene mutant affected the expression of mitochondrial morphology-related proteins, leading to excessive mitochondrial fission. In conclusion, the mutant DD genotype of the gene was an independent predictor of worse long-term prognosis for CAD patients. DD-mutant HUVECs exhibited abnormal activation of the NF-B pathway and increased Drp1 expression, which caused excessive mitochondrial fission and dysfunction, ultimately leading to increased apoptosis.
血管内皮细胞凋亡是动脉粥样硬化性心血管疾病（包括冠心病）的核心病理改变。确定内皮细胞凋亡的分子机制非常重要。核因子 kappa B（NF-κB）是控制细胞凋亡的关键转录因子。我们之前的研究表明，基因（rs28362491）启动子中的-94 ATTG ins/del 突变是冠心病的危险因素。在本研究中，我们发现基因 rs28362491 多态性与冠心病患者主要不良心脑血管事件（MACCEs）的增加呈正相关。在调整年龄、吸烟、高血压、血糖和低密度脂蛋白胆固醇等混杂因素后，突变 DD 基因型是 MACCEs 的独立预测因子（OR=2.578，95%CI=1.64-4.05，=0.003）。该研究表明，突变型人脐静脉内皮细胞（DD 突变型 HUVECs）对高糖/棕榈酸诱导的凋亡更敏感，这伴随着 p50 表达降低和 cleaved caspase-3、Cytochrome c 和磷酸化 p65 表达增加（<0.05）。线粒体膜电位显著降低，而 mtROS 水平升高，mPTP 开放增加，在 DD 突变型 HUVECs 中观察到（<0.05）。此外，与野生型细胞（基因型 II HUVECs）相比，DD 突变型 HUVECs中具有碎片化或球形线粒体的细胞比例显著升高（<0.05）。此外，在高糖/棕榈酸刺激后，基因突变显著增加了 Drp1 的表达，这表明基因突变影响了与线粒体形态相关蛋白的表达，导致过度的线粒体分裂。总之，基因的突变 DD 基因型是冠心病患者长期预后不良的独立预测因子。DD 突变型 HUVECs 表现出 NF-κB 通路的异常激活和 Drp1 表达的增加，导致过度的线粒体分裂和功能障碍，最终导致细胞凋亡增加。
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