Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes

Fu, Zhijie; Zhong, Xuezhen; Ma, Wen-Ya; Zhang, Wendong; Shi, Cheng-yao

doi:10.1016/j.bbrc.2016.11.007

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…In animal models, lipophilic statins mostly reduced arrhythmia occurrence, which was correlated with the ability of lipophilic statins to cross and modulate the composition of the plasma membrane in the myocardium 28 , 29 , 30 . Similar conclusions were drawn in a recent study regarding the ability of statins to modulate membrane ion channel composition and exert anti-inflammatory effects in monocytes (31) . In this regard, it was shown that the ability of pravastatin, as a hydrophilic statin, to exert neuroprotective effects following cerebral ischemia depended on increased blood-brain barrier permeability (32) .…”

Section: Discussionsupporting

confidence: 89%

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Bergt

Grub

Wagner

et al. 2017

JACC: Basic to Translational Science

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Section: Discussionsupporting

confidence: 89%

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Bergt

Grub

Wagner

et al. 2017

JACC: Basic to Translational Science

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“…Despite hydrophilic statins such as rosuvastatin showing strong efficacy in lowering cholesterol and preventing cardiovascular disease 77,78 , a number of studies have suggested increased benefits of lipophilic statins 20,21,79 . For instance the PRIMO study (Prédiction du Risque Musculaire en Observationnel; Prediction of Muscular Risk in Observational conditions) investigated muscular symptoms in a population of approximately 8,000 hyperlipidemic patients treated with statins 80 .…”

Section: Discussionmentioning

confidence: 99%

“…Other statins, such as fluvastatin, simvastatin and atorvastatin have different degrees of hydrophobicity 19–21 . These properties may be important in explaining some of the off-target effects of statins 20,21 . The IKs channel is formed by KCNQ1 and KCNE1 subunits and is one of the major channels responsible for cardiac repolarization.…”

Section: Introductionmentioning

confidence: 99%

Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization

Ronzier

Parks

Qudsi

et al. 2019

Sci Rep

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Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.

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“…This may be because hydrophilic statins have weaker effects on endothelial oxidative metabolism than hydrophobic statins [46] .In anti-inflammatory research, a study showed that lipophilic statins are significantly better than hydrophilic statins in improving cardiac function and reducing inflammation in patients with heart failure [47] . Moreover, lipophilic statins have been proven to inhibit Volume-activated Clchannels by inhibiting NADPH oxidase and reduce the inflammation of monocytes caused by hypotonicity, which have not been found in hydrophilic statins [48] .In the research of statins in cancer treatment, studies have shown that Lipophilic statins are more protective than hydrophilic statins for patients with pancreatic Published by Francis Academic Press, UK -11-cancer or breast cancer [49,50] . Another study of human pancreatic cancer lines, lipophilic statins have stronger effects in drug concentration of intracellular, bioavailability and genes expression changing than hydrophilic statins [51] .…”

Section: Potential Mechanisms Underlying the Inconsistency Of Statins...mentioning

confidence: 99%

Can statins be applied for treating acute respiratory distress syndrome?

2023

FMSR

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Despite decades of research, no pharmacological therapy is effective in acute respiratory distress syndrome (ARDS). Fortunately, the pharmacogenetic evidence suggests that statins can be a candidate drug for ARDS. However, concerning ARDS, the potential effects of statin are controversial. This review summarizes current progress on the studies of statins therapy in ARDS.Recent finding ARDS is a highly heterogeneous disease. Two subphenotypes, hyper-inflammation subphenotype, and hypoinflammation subphenotype have been confirmed recently. Additionally, statins have been shown to have different therapeutic effects on different subphenotypes. For instance, simvastatin can significantly improve the 28-day survival rate of the high inflammation group, whereas rosuvastatin does no effect on both subphenotypes. And during the new coronavirus epidemic, the use of statins has been reported to improve the prognosis of COVID-19 patients including those with ARDS. Existing studies suggest great potential of statins for the treatment of ARDS. However, its role in ARDS is not just as straightforward as previously thought. Further studies are urgently needed to investigate the role of statins among different ARDS subphenotypes, which is particularly important in the context of the COVID-19.

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Lipophilic but not hydrophilic statin functionally inhibit volume-activated chloride channels by inhibiting NADPH oxidase in monocytes

Cited by 5 publications

References 29 publications

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization

Can statins be applied for treating acute respiratory distress syndrome?

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