Identification of New Small Molecules as Apoptosis Inhibitors in Vascular Endothelial Cells
Identification of New Small Molecules as Apoptosis Inhibitors in Vascular Endothelial Cells
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鉴定新的小分子作为血管内皮细胞凋亡抑制剂
DOI：
10.1097/fjc.0000000000000355
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发表时间：
2016-04-01
影响因子：
3
通讯作者：
Miao, JunYing
中科院分区：
文献类型：
--
作者：
Liu, ShuYan;Kong, XiangQian;Miao, JunYing
翻译后摘要：血管内皮细胞（VEC）凋亡参与动脉粥样硬化和其他心血管疾病的发展。我们先前发现1-（2-羟基-3-芳氧基丙基）-3-芳基-1H-吡唑-5-羧酸乙酯衍生物（3a-o）在细胞命运控制中起重要作用。在本研究中，在15个化合物中，我们进一步筛选了2个化合物，3d和3k，其抑制由血清和成纤维细胞生长因子2剥夺诱导的VEC凋亡。为了阐明3d和3k的哪种手性对映体起作用，我们合成了3d-S及其对映体3d-R、3k-S及其对映体3k-R。然后，我们研究了手性化合物在血管内皮细胞中的抗肿瘤活性。3d-S、3d-R、3k-S、3k-R四种小分子均能显著提高VEC的活力，抑制VEC凋亡。此外，这些小分子还能明显降低在VEC凋亡调控中起关键作用的整合素4的水平。&bgr; 3k-S和3k-R显著增加Bcl-2/Bax比值，降低活性氧水平。因此，我们提供了新的VEC凋亡抑制剂。这些化合物可能是预防与VEC凋亡相关的血管疾病的潜在药物。
Abstract: Vascular endothelial cell (VEC) apoptosis is involved in the development of atherosclerosis and other cardiovascular diseases. We previously found that ethyl 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole -5-carboxylate derivatives (3a-o) play important roles in cell fate control. In this study, among the 15 compounds, we further screened 2 compounds, 3d and 3k, that suppressed VEC apoptosis induced by deprivation of serum and fibroblast growth factor 2. To clarify which chiral enantiomers of 3d and 3k functioned, we synthesized 3d-S and its enantiomer 3d-R, 3k-S, and its enantiomer 3k-R. Then, we investigated the apoptosis-inhibiting activity of the chiral compounds in VECs. Four small molecules, 3d-S, 3d-R, 3k-S, 3k-R, significantly elevated VEC viability and inhibited apoptosis. Furthermore, these small molecules could obviously decrease the level of integrin &bgr;4 that plays a key role in the regulation of VEC apoptosis. 3k-S and 3k-R increased Bcl-2/Bax ratio and reduced reactive oxygen species levels dramatically. Therefore, we provide new VEC apoptosis inhibitors. These compounds may be potential agents in the prevention of vascular diseases associated with VEC apoptosis.