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J Cardiovasc Pharmacol ; 50(6): 708-11, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18091590

ABSTRACT

Acute discontinuation of statins induces vascular dysfunction and increases cardiovascular events. The mechanisms underlying these events are under investigation. We showed an increase in angiotensin II (AngII) signaling after acute statin withdrawal. We investigated whether AngII-AT1-receptor expression (AT1-R mRNA) and receptor protein (AT1-R) levels mediate increased AngII signaling. In rat aortic vascular smooth muscle cells (VSMC), simvastatin (0.3 to 3 microM for 24 hours) resulted in concentration-dependent inhibition of AngII-stimulated phosphorylation of extracellular-signal regulated kinase 1/2 ERK1/2 (-67 +/- 5% with 3 microM; P < 0.001) and decreased AT1-R mRNA (-34 +/- 8% with 3 microM; P < 0.01) and AT1-R protein (-32 +/- 6% with 3 microM; P < 0.01). Removal of simvastatin led to a rebound increase in mRNA-AT1-R (+39 +/- 2%, P < 0.01), AT1-R protein (+46 +/- 2%; P < 0.01), and AngII-mediated phosphorylation of ERK1/2 (+36 +/- 3%; P < 0.01). The increase in receptor expression was present at 1 hour and lasted for 4 hours, whereas increased AT1-R protein and AngII signaling started at 2 hours and lasted for nearly 2 hours. In summary, increased AngII signaling after statin withdrawal is most likely due to increases in AT1-R number due to increased transcription. The increase in AngII activity may contribute to the vascular dysfunction associated with statin withdrawal.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Myocytes, Smooth Muscle/drug effects , Receptor, Angiotensin, Type 1/metabolism , Simvastatin/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Blotting, Western , Cells, Cultured , Dose-Response Relationship, Drug , Male , Mitogen-Activated Protein Kinase 1/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Phosphorylation/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Time Factors , Up-Regulation/drug effects
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