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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

By Luciana V. Rossoni, Mark Wareing, Camilla F. Wenceslau, Mahmood Al-Abri, Chris Cobb and Clare Austin

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

Topics: Research Article
Publisher: Portland Press Ltd.
OAI identifier: oai:pubmedcentral.nih.gov:3174052
Provided by: PubMed Central

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Citations

  1. (2011). accepted 14
  2. (2010). Activation of AMP-activated protein kinase by 5-aminoimidazole-
  3. (1999). Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.
  4. (2004). Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors.
  5. (2000). Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo.
  6. (2003). Acute vasodilator effects of HMG-CoA reductase inhibitors: involvement of PI3-kinase/Akt pathway and Kv channels.
  7. (2003). Adiponection stimulates production of nitric oxide in vascular endothelial cells.
  8. (2009). AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633..
  9. (2007). AMP-activated protein kinase in metabolic control and insulin signalling.
  10. (2009). AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease.
  11. (1999). AMP-activated protein kinase phosphorylation of endothelial NO synthase.
  12. (1999). An in vitro study of the hydroxyl radical scavenging property of fluvastatin, and HMG-CoA reductase inhibitor.
  13. carboxamide-1-β-d-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion.
  14. (2002). Cerivastatin potentiates nitric oxide release and eNOS expression through inhibition of isoprenoids synthesis.
  15. (1996). Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase.
  16. (2009). Chronic ouabain treatment exacerbates blood pressure elevation in spontaneously hypertensive rats: the role of vascular mechanisms.
  17. (1977). Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats.
  18. (2003). Direct activation of AMP-activated protein kinase stimulates nitric oxide synthesis in human aortic endothelial cells.
  19. (2002). Direct in vivo evidence of a vascular statin: a single does of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects.
  20. (2002). Disabling a C-terminal autoinhibitory control element in endothelial nitric-oxide synthase by phosphorylation provides a molecular explanation for activation of vascular NO synthesis by diverse physiological stimuli.
  21. (2008). Effects of different statins on endothelial nitric oxide synthase and Akt phosphorylation in endothelial cells.
  22. (2004). eNOS at a glance.
  23. (1998). Erythromicin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.
  24. (1998). Grapefruit juice-simvastatin interaction: effect of serum concentrations of simvastatin, simvastatin acid and HMG-CoA reductase inhibitors.
  25. (2006). Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.
  26. (2008). Increase in phosphorylation of Akt and its downstream signalling targets and suppression of apoptosis by simvastatin after traumatic brain injury.
  27. (2009). JUPITER: major implications for vascular risk assessment.
  28. (2006). Justification for the use of statins in primary prevention: an intervention trial evaluating rosuvastatin (JUPITER): can C-reactive protein be used to target statin therapy in primary prevention?
  29. (2000). Mechanisms of 17β-oestradiol induced vasodilatation in isolated pressurised rat small arteries.
  30. (1995). Mechanisms of protein prenylation and role in G protein function.
  31. (1998). Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
  32. (2002). MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
  33. (1998). Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase.
  34. (2009). Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase.
  35. (2000). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.
  36. (2009). Regulation of Rac1 by simvastatin in endothelial cells: differential roles of AMP-activated protein kinase and calmodulin-dependent kinase kinase-β.
  37. (2005). Rho GTPases, statins and nitric oxide.
  38. ScandinavianSimvastatinSurvivalStudyInvestigators(1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S).
  39. (2009). Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: a dose-response effect dependent on endothelial nitric oxide synthase.
  40. (2008). Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase.
  41. (1997). Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation
  42. (2006). Statins activate AMP-activated protein kinase in vitro and in vivo.
  43. (2007). Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.
  44. (1997). The AMP-activated protein kinase-fuel gauge of the mammalian cell?
  45. (2011). The Authors Journal compilation C
  46. (1995). The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.
  47. (1998). Upregulation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Circulation 97,