Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation

Li, Xiaoxia; Wang, Peihua; Xu, Xizhen; Wang, Yong; Xia, Yong; Wang, Daowen

doi:10.1007/s11596-009-0304-0

Cited by 9 publications

(6 citation statements)

References 24 publications

(29 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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“…The possible mechanisms responsible for the above effects have been discussed widely (Jasińska et al . 2007) and may involve an increase in NO production or a decrease in AT1 expression [23-25]. However, the BP-lowering effects of statins are observed mainly in hypertensive patients.…”

Section: Discussionmentioning

confidence: 99%

The influence of high-dose simvastatin and diltiazem on myocardium in rabbits: a haemodynamic study

Jasińska

Owczarek²,

Orszulak–Michalak³

2011

aoms

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IntroductionSimvastatin and diltiazem are often prescribed together for the treatment of hypercholesterolaemia in patients with hypertension and/or angina pectoris. However, diltiazem, a CYP3A inhibitor, is a well-recognized risk factor of skeletal muscle myopathy. It is not known whether such interaction also affects myocardial efficiency causing haemodynamic changes. The aim of the experiment was to establish the impact of simvastatin co-administered with diltiazem on the haemodynamic parameters after continuous infusion of dopamine.Material and methodsThe experiments were performed on 28 New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC – methylcellulose (control group); diltiazem; simvastatin; simvastatin + diltiazem, for 14 days (po). The following haemodynamic parameters were estimated: cardiac output index (CI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of haemodynamic parameters was performed by the Doppler method and during the experiments the animals were anaesthetized with α-chloralose (75 mg/kg bw) and urethane (500 mg/kg bw).ResultsDopamine did not cause a statistically significant increase in CI in rabbits receiving simvastatin alone. Diltiazem significantly increased CI if given simultaneously with simvastatin, which might suggest the improvement of cardiac efficiency resulting from such interaction.ConclusionsThe possibility of another mechanism of drug-drug interaction than the one based on CYP3A inhibition, and its impact on cardiac or skeletal muscle, might be considered.

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“…Evidence of statins increasing the activity of eNOS is not a novel discovery and has been shown to improve nitric oxide release and reduced free radical scavenging of nitric oxide [195]. Simvastatin was described to significantly enhance eNOS without changing its expression (i.e., without gene upregulation) possibly via phosphorylation by protein kinase B (Akt/PKB) and/or AMP-activated protein kinase (AMPK) [196]. Cerivastatin was seen to activate calcium-activated potassium channels in human endothelial cells, which also contributes to statin-induced nitric oxide production [197].…”

Section: Future Implications Of Statinsmentioning

confidence: 99%

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

Murphy

Deplazes

Cranfield

et al. 2020

IJMS

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Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

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Simvastatin increases the activity of endothelial nitric oxide synthase via enhancing phosphorylation

Cited by 9 publications

References 24 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

The influence of high-dose simvastatin and diltiazem on myocardium in rabbits: a haemodynamic study

The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins

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