Tumor necrosis factor alpha (TNF alpha) plays an essential role in the regulation of vascular smooth muscle cell (VSMC) phenotype. In the present study, we provide evidence that kruppel-like factor 5 (KLF5) plays an essential role in TNF alpha-induced phenotypic conversion of VSMCs. Ectopic expression of KLF5 completely blocked phenotypic conversion of VSMCs from synthetic to contractile type. In addition, stimulation of VSMCs with TNF alpha facilitated expression of KLF5, whereas expression of smooth muscle marker genes such as SM22 alpha: and smooth muscle actin (SMA) was significantly down-regulated. TNF alpha significantly enhanced the promoter activity of KLF5 as well as mRNA level, which is significantly suppressed by the inhibition of the MAPK pathway. Silencing of KLF5 suppressed TNF alpha-induced phenotypic conversion of VSMCs, whereas overexpression of KLF5 stimulated phenotypic conversion of VSMCs and facilitated the loss of angiotensin II (AngII)-dependent contraction. Finally, overexpression of KLF5 significantly attenuated the promoter activity of SM22 alpha and SMA. Therefore, we suggest that TNF alpha-dependent induction of KLF5 may play an essential role in phenotypic modulation of VSMCs. (C) 2015 Elsevier Inc. All rights reserved.