Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries.

Luciana V Rossoni , Mark Wareing , Camilla Wenceslau , Mahmood Al-Abri , Christopher Cobb , Clare E Austin (1)

1 Cardiovascular Research Group

Statins can have beneficial cholesterol-independent effects on vascular contractility which may involve increases in the bioavailability of nitric oxide (NO) as a result of phosphorylation of endothelial NO synthase. While this has been attributed to phosphorylation of Akt, studies in cultured cells have shown that statins can phosphorylate AMPK; 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 hours) with simvastatin (0.1 or 1 μM) on contractile responses were examined in the presence and absence of N-Nitro-L-arginine (L-NNA, 10 μM) or mevalonate (1 mM). Effects on endothelial NO synthase (eNOS), phosphorylated eNOS (Ser 1177) and total and phosphorylated 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 hours) significantly reduced constriction to U46619 and phenylephrine and enhanced dilations to 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 AMPKa phosphorylation but had no effect on Akt protein expression and phosphorylation after 2 hours incubation. Compound C prevented the effects of simvastatin on eNOS phosphorylation and contractility. Thus, simvastain can acutely modulate resistance arterial contractile function via mechanisms which involve the AMPK/ pSer1177eNOS/ NO-dependent pathway.

Mots clés: Medicine

Domaines: Médecine humaine et pathologie

Luciana V Rossoni, Mark Wareing, Camilla Wenceslau, Mahmood Al-Abri, Christopher Cobb, et al.. Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries.. Clinical Science, 2011, 121 (10), pp.449-458. ⟨10.1042/CS20110259⟩. ⟨hal-00720574⟩