ANGIOTENSIN-II DOWN-REGULATES THE VASCULAR SMOOTH-MUSCLE AT(1) RECEPTOR BY TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MECHANISMS - EVIDENCE FOR HOMOLOGOUS AND HETEROLOGOUS REGULATION

The vascular angiotensin II (ANG II) receptor (AT(1)) is a central com ponent of the renin-angiotensin system; thus, regulation of its expres sion is likely to be important in cardiovascular responsiveness. We de monstrate that ANG II down-regulates its receptor in rat aortic vascul ar smooth muscle cells. Incubation for 4 hr with 100 nM ANG II decreas ed AT(1) mRNA and protein by 70% and 35%, respectively. This homologou s down-regulation was concentration and time dependent and was blocked by the AT(1) antagonist losartan. It did not appear to be mediated by protein kinase C or other protein kinases but was dependent on the su stained signaling pathway sensitive to phenylarsine oxide. Heterologou s down-regulation was observed with the agonists alpha-thrombin and AT P and the cAMP-increasing agent forskolin. ANG II inhibited transcript ion by 50% and destabilized the AT(1) mRNA. Down-regulation of AT(1) m RNA was blocked by transcription and translation inhibitors, suggestin g that it required expression of a protein factor or factors. These re sults indicate that ANG II down-regulates its vascular receptor by bot h transcriptional and post-transcriptional mechanisms. Homologous and heterologous down-regulation of the AT(1) receptor may participate in the coordinated physiological adaptation of vascular tone to vasoactiv e hormones.