Effects of different statins on endothelial nitric oxide synthase and AKT phosphorylation in endothelial cells

Wang, Juyong; Xu, Zhen-ye; Kitajima, Isao; Wang, Zhongqi

doi:10.1016/j.ijcard.2007.10.034

Cited by 20 publications

(16 citation statements)

References 32 publications

(41 reference statements)

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“…aortic endothelial layer in vivo. This is in stark contrast with in vitro studies, which clearly show that statins can phosphorylate eNOS at these sites [32][33][34] .…”

Section: Discussioncontrasting

confidence: 66%

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

Arora

Hare

Zulli

2012

JAT

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In vivo evidence for the pleiotropic effects of simvastatin on the nitric oxide synthase system is limited. Aims: To determine if simvastatin can affect the endothelial nitric oxide synthase cascade. Methods: New Zealand white rabbits (n=15) were divided: Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine (M) plus 0.5% cholesterol (C) and 5% peanut oil (atherogenic diet); Group 3 received the same diet as the MC group plus 5 mg/kg/ day simvastatin (S) orally (MCS). After 4 weeks, the abdominal aorta was collected and analyzed.

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“…aortic endothelial layer in vivo. This is in stark contrast with in vitro studies, which clearly show that statins can phosphorylate eNOS at these sites [32][33][34] .…”

Section: Discussioncontrasting

confidence: 66%

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

Arora

Hare

Zulli

2012

JAT

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“…These mechanisms may include changes in the expression of eNOS mRNA and protein [26–28], reductions in NO breakdown [29] and, of particular importance in endothelial cells, post-translational modification of eNOS activity by phosphorylation [9–13,30,31]. It is well established that phosphorylation of eNOS at Ser 1177 increases its activity [9].…”

Section: Discussionmentioning

confidence: 99%

“…The most widely studied eNOS phosphorylation pathway involves the serine/threonine Akt and it is widely accepted that activation of Akt by phosphorylation (Ser 473 ) may also modulate vascular contractility in an eNOS-dependent manner [10,32,33]. Previous studies have shown that treatment of cultured endothelial cells with simvastatin causes rapid phosphorylation of both Akt and eNOS increasing the activity of the latter [11–13]. Such effects are thought to contribute to the acute effects of cerivastatin on endothelial function in isolated rat aorta [34].…”

Section: Discussionmentioning

confidence: 99%

“…The most widely studied phosphorylation pathway involves the serine/threonine Akt (also known as protein kinase B), which can phosphorylate eNOS on Ser 1177 , resulting in activation of the enzyme and increased production of NO [10,11]. Statin modulation of eNOS activity via this pathway has been demonstrated in cultured endothelial cells, although this is not a uniform finding [12,13]. AMPK (AMP-activated protein kinase) is another serine/threonine kinase that has long been known to play a central role in the regulation of energy homoeostasis [14].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2011

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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.

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“…Actinomycin treatment revealed that statins also increased the half-life of eNOS mRNA, supporting the concept that upregulation of eNOS by statins occurs via a posttranscriptional mechanism. Other studies showed that statins increased eNOS activity via activation of the PI3/Akt kinase pathway, resulting in upregulation of eNOS, increased cGMP production, and NO biosynthesis 173,174…”

Section: Introductionmentioning

confidence: 99%

Vascular nitric oxide: formation and function

Jin

Loscalzo

2010

JBM

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Nitric oxide (NO) is a structurally simple, highly versatile molecule that was originally discovered over 30 years ago as an endothelium-derived relaxing factor. In addition to its vasorelaxing effects, NO is now recognized as a key determinant of vascular health, exerting antiplatelet, antithrombotic, and anti-inflammatory properties within the vasculature. This short-lived molecule exerts its inhibitory effect on vascular smooth muscle cells and platelets largely through cyclic guanosine monophosphate-dependent mechanisms, resulting in a multitude of molecular effects by which platelet activation and aggregation are prevented. The biosynthesis of NO occurs via the catalytic activity of NO synthase, an oxidoreductase found in many cell types. NO insufficiency can be attributed to limited substrate/cofactor availability as well as interactions with reactive oxygen species. Impaired NO bioavailability represents the central feature of endothelial dysfunction, a common abnormality found in many vascular diseases. In this review, we present an overview of NO synthesis and biochemistry, discuss the mechanisms of action of NO in regulating platelet and endothelial function, and review the effects of vascular disease states on NO bioavailability.

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Effects of different statins on endothelial nitric oxide synthase and AKT phosphorylation in endothelial cells

Cited by 20 publications

References 32 publications

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

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

Vascular nitric oxide: formation and function

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