Synthetic retinoid Am80 inhibits interaction of KLF5 with RAR¦Á through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells

In the present study, we show that Am80 inhibited the interaction between Kr¨ppel‐like factor 5 (KLF5) and RAR¦Á and this inhibitory effect was accompanied by the dephosphorylation of KLF5 in vascular smooth muscle cells (VSMCs). Treating VSMCs with LY294002, the PI3K/Akt inhibitor, abrogated Am80‐induced KLF5 dephosphorylation and reversed Am80‐induced suppression of interaction between KLF5 and RAR¦Á, whereas treating VSMCs with SB203580, the p38 kinase inhibitor, further attenuated the interaction between KLF5 and RAR¦Á. Constitutively active p38 kinase MKK6b infection prevented the KLF5 dephosphorylation induced by Am80. This study suggests that Am80 induces KLF5 dephosphorylation by activating PI3K/Akt signaling, and inhibits KLF5 phosphorylation by blocking p38 signaling, subsequently leading to the suppression of interaction of KLF5 with RAR¦Á. In conclusion£¬ we showed that Am80 significantly induces RAR¦Á expression and inhibits KLF5 expression and the interaction of KLF5 with RAR¦Á at the cellular and tissue level. Furthermore, we established that this action of Am80 is mediated by activating the PI3K/Akt pathway and inhibiting the p38 MAPK pathway. These results provide novel insight not only into the molecular mechanism by which Am80 inhibits the interaction between KLF5 and RAR¦Á but also a specific therapeutic target for vascular remodeling in diseases such as atherosclerosis.