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Background  Kruppel‐like factor 2 ( KLF 2) 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  KLF 2, modulating  KLF 2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.    Methods and Results  High‐throughput drug screening based on  KLF 2 promoter luciferase reporter assay was performed to screen  KLF 2 activators. Real‐time  PCR  and western blot were used to detect gene and protein expression. Identified  KLF 2 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  KLF 2 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  KLF 2 dependent using  KLF 2‐deficient mouse lung endothelial cells or  KLF 2 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.    Conclusions  These results demonstrate that  SAHA  has  KLF 2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that  KLF 2 activation could be a promising therapeutic strategy for treating atherosclerosis.

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis