KLF5 is involved in Ang II‐induced VSMC proliferation through trans‐activating cyclin D1 expression

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Kr̈¹ ppel‐like transcription factor 5 (KLF5) plays key roles in regulating cell proliferation and differentiation. In this work, we reported that Ang II stimulated KLF5 expression with concurrent acceleration of the cell cycle progression in vascular smooth muscle cells (VSMCs). The overexpression of KLF5 also increased the expression of cyclin D1 and proliferation in VSMCs. Conversely, silencing KLF5 expression abrogated the inducing effects of Ang II on KLF5 and cyclin D1 expression, and neutralized the Ang II‐induced VSMC proliferation. KLF5 plays a crucial role in Ang II‐induced cyclin D1 expression and proliferation of VSMCs. Furthermore, we also showed that the Ang II stimulated the activity of KLF5 by inducing its phosphorylation mediated by the ERK 1/2 and p38 MAPK pathways. A specific interaction was found between KLF5 and c‐Jun, which enhances binding activity of the both proteins in cyclin D1 promoter, and consequently leads to a synergistic increase in the transcription of cyclin D1 gene that is important for cell cycle progression and cell proliferation. Cotransfection of KLF5 and c‐Jun expression vectors significantly increased the cyclin D1 promoter activity by over 5‐fold. These results indicate that KLF5 plays a positive regulatory effect on cell cycle progression and proliferation through trans‐activating cyclin D1 expression via synergistic interaction with c‐Jun in Ang II‐induced VSMCs.