Retinoids inhibit the actions of angiotensin II on vascular smooth muscle cells

Retinoids are derivatives of vitamin A and powerful inhibitors of cell prol iferation and inflammation. Angiotensin II (Ang II) contributes to vascular lesions by promoting cell growth of vascular smooth muscle cells (VSMCs). Therefore, we examined whether retinoids interfere with the proproliferativ e actions of Ang II in VSMCs via AT(1) receptor-dependent or activator prot ein-1 (AP-1)-dependent mechanisms. VSMCs express retinoid receptor proteins , ie, retinoic acid receptor (RAR) alpha and retinoid X receptor (RXR) alph a. Long-term exposure to 1 mu mol/L all-trans retinoic acid (RA) dose-depen dently inhibited Ang II-induced cell proliferation (P<0.005) as well as DNA and protein synthesis (P<0.001). All-trans RA blocked Ang II stimulation o f transforming growth factor-beta (1) mRNA (P<0.005). All-trans RA inhibiti on of vascular VSMC growth was mediated both via RAR- and RXR-dependent pat hways, as shown by receptor-specific synthetic retinoids. Transfection expe riments revealed that inhibition of AP-1-dependent gene transcription is on e mechanism by which all-trans RA inhibits Ang II action. RAR<alpha> cotran sfection enhanced the anti-AP-1 effects of all-trans RA dose-dependently, A P-1 activity was similarly inhibited by cotransfection with either RAR alph a or RXR alpha. Ang II-induced gene expression of c-fos was abrogated by al l-trans RA treatment (P<0.005). In VSMCs, all-trans RA downregulated AT(1) receptor mRNA (P<0.01) and reduced B-max (P<0.001). All-trans RA repressed Ang II-stimulated AT(1) receptor promoter activity. The all-trans RA inhibi tory effect was abolished when the AP-1 consensus site on the AT(1) recepto r promoter was deleted. Our findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. The findings support the noti on that retinoids may interfere with proliferative vascular disease.