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Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries
- Source :
- Clinical Science (London, England : 1979)
- Publication Year :
- 2011
-
Abstract
- Statins can have beneficial cholesterol-independent effects on vascular contractility, which may involve increases in the bioavailability of NO (nitric oxide) as a result of phosphorylation of eNOS (endothelial NO synthase). Although this has been attributed to phosphorylation of Akt (also known as protein kinase B), studies in cultured cells have shown that statins can phosphorylate AMPK (AMP-activated protein kinase); it is unknown whether this has functional effects in intact arteries. Thus we investigated the acute effects of simvastatin on resistance arterial contractile function, evaluating the involvement of NO, Akt and AMPK. Isolated rat mesenteric resistance arteries were mounted on a wire myograph. The effects of incubation (1 and 2 h) with simvastatin (0.1 or 1 μM) on contractile responses were examined in the presence and absence of L-NNA (N-nitro-L-arginine; 10 μM) or mevalonate (1 mM). Effects on eNOS, phospho-eNOS (Ser1177), and total and phospho-Akt and -AMPK protein expression were investigated using Western blotting. The effect of AMPK inhibition (compound C, 10 μM) on eNOS phosphorylation and contractile responses were also studied. Simvastatin (1 μM, 2 h) significantly reduced constriction to U46619 and phenylephrine and enhanced dilations to ACh (acetylcholine) in depolarized, but not in U46619-pre-constricted arteries. These effects were completely and partially prevented by L-NNA and mevalonate respectively. Simvastatin increased eNOS and AMPKα phosphorylation, but had no effect on Akt protein expression and phosphorylation after 2 h incubation. Compound C prevented the effects of simvastatin on eNOS phosphorylation and contractility. Thus simvastain can acutely modulate resistance arterial contractile function via mechanisms that involve the AMPK/phospho-eNOS (Ser1177)/NO-dependent pathway.
- Subjects :
- Male
L-NNA, N-nitro-L-arginine
Simvastatin
KPSS, potassium PSS
AICAR, 5-amino-4-imidazolecarboxamide riboside
AMP-Activated Protein Kinases
Tissue Culture Techniques
AMP-activated protein kinase
Enos
Vasoconstrictor Agents
Phosphorylation
Mesenteric arteries
HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA
biology
eNOS, endothelial NO synthase
General Medicine
Mesenteric Arteries
medicine.anatomical_structure
SNP, sodium nitroprusside
Research Article
medicine.medical_specialty
S1
Nitric Oxide Synthase Type III
S9
Nitric Oxide
Contractility
Internal medicine
resistance artery
medicine
Animals
Rats, Wistar
Protein kinase A
Protein kinase B
Dose-Response Relationship, Drug
ACh, acetylcholine
PSS, physiological salt solution
statin
AMPK
biology.organism_classification
acetylcholine
Rats
AMPK, AMP-activated protein kinase
Endocrinology
Vasoconstriction
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
biology.protein
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 14708736
- Volume :
- 121
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Clinical science (London, England : 1979)
- Accession number :
- edsair.doi.dedup.....91017361c382ee5f5dc929a8e6e231ec