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.
journal_name
J Cardiovasc Pharmacoljournal_title
Journal of cardiovascular pharmacologyauthors
Castejon AM,Zollner E,Tristano AG,Cubeddu LXdoi
10.1097/FJC.0b013e318157c0b2subject
Has Abstractpub_date
2007-12-01 00:00:00pages
708-11issue
6eissn
0160-2446issn
1533-4023pii
00005344-200712000-00016journal_volume
50pub_type
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