Angiotensin II down-regulates the vascular smooth muscle AT1 receptor by transcriptional and post-transcriptional mechanisms: evidence for homologous and heterologous regulation
Lassègue, B.; Alexander, R.W.; Nickenig, G.; Clark, M.; Murphy, T.J.; Griendling, K.K.
Molecular Pharmacology 48(4): 601-609
1995
ISSN/ISBN: 0026-895X PMID: 7476884 Document Number: 440341
The vascular angiotensin II (ANG II) receptor (AT-1) is a central component of the renin-angiotensin system; thus, regulation of its expression is likely to be important in cardiovascular responsiveness. We demonstrate that ANG II down-regulates its receptor in rat aortic vascular smooth muscle cells. Incubation for 4 hr with 100 nm ANG II decreased AT-1 mRNA and protein by 70% and 35%, respectively. This homologous 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 sustained signaling pathway sensitive to phenylarsine oxide. Heterologous down-regulation was observed with the agonists alpha-thrombin and ATP and the cAMP-increasing agent forskolin. ANG II inhibited transcription by 50% and destabilized the AT-1 mRNA. Down-regulation of AT-1 mRNA was blocked by transcription and translation inhibitors, suggesting that it required expression of a protein factor or factors. These results indicate that ANG II down-regulates its vascular receptor by both 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 vasoactive hormones.