Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction
Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction
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DOI：
10.1093/cvr/cvt062
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发表时间：
2013-07-01
影响因子：
10.8
通讯作者：
Chen, Chu-Huang
中科院分区：
文献类型：
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作者：
Chang, Po-Yuan;Chen, Yi-Jie;Chen, Chu-Huang
L5是人低密度脂蛋白（LDL）中带负电荷最多的亚段，也是LDL中唯一能够通过抑制成纤维细胞生长因子-2 （FGF2）转录诱导培养血管内皮细胞（ECs）凋亡的亚段。我们研究了st段抬高型心肌梗死（STEMI）患者血浆L5水平是否升高，以及阿司匹林是否对暴露于L5的人冠状动脉ECs （HCAECs）提供表观遗传保护。比较STEMI患者（n 10）和胸痛综合征但冠状动脉造影正常的对照组（n 5）的血浆L5水平。从STEMI患者和对照组的血浆中分离L5，并在L5和阿司匹林治疗的hcaec中检测细胞凋亡、FGF2表达和FGF2启动子甲基化。STEMI患者血浆L5水平显著高于对照组（P < 0.001）。用L5治疗hcaec导致存活和FGF2表达降低，FGF2启动子CpG甲基化增加。L5与低浓度阿司匹林（0.2 mM）联合治疗HCAEC可减轻L5对HCAEC存活、FGF2表达和FGF2启动子甲基化的不良影响。相反，高浓度阿司匹林（1.0 mM）强化了L5的作用。我们的研究结果表明，L5水平在STEMI患者中显著升高。此外，L5通过FGF2启动子的CpG甲基化损害HCAEC功能，而FGF2启动子在低浓度阿司匹林存在下被抑制。我们的研究结果为阿司匹林预防心肌梗死的新机制提供了证据。
L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5.Plasma L5 levels were compared between patients with STEMI (n 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (1.0 mM) accentuated the effects of L5.Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.