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Kr̈¹ppel‐like factor 4 inhibits RAR α‐mediated signaling transduction in vascular smooth muscle cells

Proliferation inhibition of vascular smooth muscle cells (VSMCs) is governed by the activity of a transcription factor network. Both the Kr¨ppel‐like factor family member Klf4 and retinoic acid receptor (RAR α) are components of such a network. However, the relationship between Klf4 and RAR α in mediating proliferation‐inhibitory effects in VSMCs remains unknown. Here, we investigated the mechanisms whereby Klf4 mediates the feedback loop of the growth‐inhibitory effects of the RAR α. We used chromatin immunoprecipitation to show that Klf4 binds to the 5¡ä regulatory region of RARα, down‐regulates RAR α expression, and specifically inhibits RARα ‐mediated PI3K‐ERK signaling. We also showed that regulation of growth inhibition by Klf4 is dependent on RARα‐PI3K‐ERK signaling since the growth‐inhibitory response to Klf4 is blocked by PI3K‐ERK inhibition. Further, we demonstrated that Klf4 is itself regulated by the PI3K pathway. Thus, Klf4 regulates RARα‐mediated PI3K‐ERK signaling and is itself downstream of PI3K‐ERK signaling. This provides a novel mechanism for signal amplification or suppression and for the control of growth‐inhibitory effects in VSMCs. Moreover, the results of this study suggest that Klf4 is one of the key mediators of retinoid actions in VSMCs.