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

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.