Suberanilohydroxamic Acid as a Pharmacological Kruppel-Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis.
Suberanilohydroxamic Acid as a Pharmacological Kruppel-Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis.
复制标题
suberanilohydroxamic Acid作为药理学Kruppel样因子2激活剂，抑制血管炎症和动脉粥样硬化。
DOI：
10.1161/jaha.117.007134
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发表时间：
2017-11-30
影响因子：
5.4
通讯作者：
Jin ZG
中科院分区：
文献类型：
--
作者：
Xu Y;Xu S;Liu P;Koroleva M;Zhang S;Si S;Jin ZG
Kruppel样因子2（KLF 2）是一种重要的锌指转录因子，通过其在内皮细胞中的抗炎、血栓形成、氧化和增殖作用维持内皮细胞的稳态。鉴于KLF 2的强有力的血管保护作用，调节KLF 2的表达或功能可能会产生新的治疗策略来治疗心血管疾病。进行基于KLF 2启动子荧光素酶报告基因测定的高通量药物筛选以筛选KLF 2激活剂。采用真实的-time PCR和western blot检测基因和蛋白表达。经口给予ApoE−/−小鼠已鉴定的KLF 2激活剂，以评价抗动脉粥样硬化疗效。通过筛选Spectrum库中的2400种化合物，我们确定了辛二酰异羟肟酸（SAHA），也称为伏立诺他，作为通过肌细胞增强因子2的药理学KLF 2激活剂。我们发现，SAHA具有抗炎作用，并减弱单核细胞与肿瘤坏死因子α致炎的内皮细胞的粘附。我们使用KLF 2缺陷型小鼠肺内皮细胞或KLF 2小干扰RNA缺失型人内皮细胞进一步表明，SAHA对内皮炎症和随后的单核细胞粘附的抑制作用是KLF 2依赖性的。重要的是，我们观察到SAHA口服给药可减少ApoE−/−小鼠中饮食诱导的动脉粥样硬化病变的发展，而对血脂水平无显著影响。这些结果表明，SAHA在内皮细胞中具有KLF 2依赖性抗炎作用，并提供了KLF 2激活可能是治疗动脉粥样硬化的有前景的治疗策略的概念证据。
Kruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases. High‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels. These results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.