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.

miR-92a regulates the expression levels of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 3 via sirtuin 1 signaling in hydrogen peroxide-induced vascular smooth muscle cells

“…Primary VSMCs were isolated from SD rat thoracic aortas, as described previously (19). In brief, animals were sacrificed by intraperitoneal injection of 2% pentobarbital sodium (50 mg/kg; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) and perfused with saline for 5 min.…”

Current knowledge of Krüppel-like factor 5 and vascular remodeling: providing insights for therapeutic strategies

“…The cross-regulation of KLF8 and KLF5 is also detected in the TNF-α-induced phenotypic switch of VSMCs. Suppressed KLF8 expression and increased KLF5 expression contribute to the reverse of contractile phenotype ( Ha et al, 2017 ). In vein graft, VSMC phenotype switch is a significant component of pathological adaption.…”

MiR-9 promotes the phenotypic switch of vascular smooth muscle cells by targeting KLF5

“…In addition, we found the expression trend among different groups of KLF5 was consistent when b-actin was regarded as the housekeeping gene (Supplementary Figure 2B). A molecule present downstream of KLF5, myocardin, is considered a key modulator for VSMC differentiation marker genes (10). A previous study has demonstrated that KLF5 negatively regulates myocardin (21).…”

“…KLF5, a member of the family of Kruppel-like factors, belongs to a group of transcription factors containing zinc finger domains, and serves as a transcriptional activator or repressor, regulating a variety of physiological processes, including differentiation, development, and proliferation (7,8). However, KLF5 is also modulated by a variety of biological mechanisms, including microRNA, and other transcriptional factors (9)(10)(11). Previous studies have demonstrated that KLF5 might contribute to VSMC dedifferentiation and synthetic phenotype change in balloon-injured artery and platelet-derived growth factor (PDGF)-stimulated VSMCs (9).…”