title: Regulation of vascular smooth muscle phenotype by cross-regulation of krüppel-like factors.
abstract: Regulation of vascular smooth muscle cell (VSMC) phenotype plays an essential role in many cardiovascular diseases. In the present study, we provide evidence that krüppel-like factor 8 (KLF8) is essential for tumor necrosis factor α (TNFα)-induced phenotypic conversion of VSMC obtained from thoracic aorta from 4-week-old SD rats. Stimulation of the contractile phenotype of VSMCs with TNFα significantly reduced the VSMC marker gene expression and KLF8. The gene expression of KLF8 was blocked by TNFα stimulation in an ERK-dependent manner. The promoter region of KLF8 contained putative Sp1, KLF4, and NFκB binding sites. Myocardin significantly enhanced the promoter activity of KLF4 and KLF8. The ectopic expression of KLF4 strongly enhanced the promoter activity of KLF8. Moreover, silencing of Akt1 significantly attenuated the promoter activity of KLF8; conversely, the overexpression of Akt1 significantly enhanced the promoter activity of KLF8. The promoter activity of SMA, SM22α, and KLF8 was significantly elevated in the contractile phenotype of VSMCs. The ectopic expression of KLF8 markedly enhanced the expression of SMA and SM22α concomitant with morphological changes. The overexpression of KLF8 stimulated the promoter activity of SMA. Stimulation of VSMCs with TNFα enhanced the expression of KLF5, and the promoter activity of KLF5 was markedly suppressed by KLF8 ectopic expression. Finally, the overexpression of KLF5 suppressed the promoter activity of SMA and SM22α, thereby reduced the contractility in response to the stimulation of angiotensin II. These results suggest that cross-regulation of KLF family of transcription factors plays an essential role in the VSMC phenotype.
authors.affiliation: Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ha
authors.affiliation: Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Sung Ji
authors.initials: SJ
authors.lastname: Yun
authors.affiliation: Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Jin
authors.affiliation: Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Physics, Dong-A University, Busan 49315, Korea.
authors.forename: Sun Ja
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan 50612, Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: Gene and Cell Therapy for Vessel-Associated Disease, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
keywords: Angiotensin; Krüppel-like factor; Phenotype; Transcription; Vascular smooth muscle cell