Abstract
The vascular angiotensin II (ANG II) receptor (AT1) 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 AT1 mRNA and protein by 70% and 35%, respectively. This homologous down-regulation was concentration and time dependent and was blocked by the AT1 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 AT1 mRNA. Down-regulation of AT1 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 AT1 receptor may participate in the coordinated physiological adaptation of vascular tone to vasoactive hormones.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Angiotensin II / pharmacology*
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Angiotensin Receptor Antagonists
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Animals
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Autoradiography
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Base Sequence
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Biphenyl Compounds / pharmacology
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Calcium / metabolism
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Cyclic AMP / metabolism
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Cytoplasm / metabolism
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Dactinomycin / pharmacology
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Down-Regulation / drug effects
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Enzyme Activation / drug effects
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Imidazoles / pharmacology
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Losartan
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Molecular Sequence Data
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Muscle Proteins / metabolism
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / ultrastructure*
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Processing, Post-Translational / drug effects*
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Protein Synthesis Inhibitors / pharmacology
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Purinergic P1 Receptor Agonists
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Purinergic P2 Receptor Agonists
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Angiotensin / genetics
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Receptors, Angiotensin / metabolism*
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Receptors, Purinergic P1 / physiology
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Receptors, Purinergic P2 / physiology
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Signal Transduction / drug effects
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Tetrazoles / pharmacology
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Transcription, Genetic / drug effects*
Substances
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Angiotensin Receptor Antagonists
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Biphenyl Compounds
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Imidazoles
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Muscle Proteins
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Protein Synthesis Inhibitors
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Purinergic P1 Receptor Agonists
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Purinergic P2 Receptor Agonists
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RNA, Messenger
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Receptors, Angiotensin
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Receptors, Purinergic P1
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Receptors, Purinergic P2
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Tetrazoles
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Angiotensin II
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Dactinomycin
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Adenosine Triphosphate
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Cyclic AMP
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Protein Kinase C
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Losartan
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Calcium