Statine

Résumé

Les statines (ou inhibiteurs de la HMG-CoA réductase) forment une classe d'hypolipémiants, utilisés comme médicaments pour baisser la cholestérolémie, notamment en maladie cardiovasculaire à cause de leur hypercholestérolémie. Consommées , les statines sont parmi les médicaments les plus vendus au monde. Leur efficacité et leur innocuité font l'objet de controverses. Membres Les statines comprennent :

l'atorvastatine (1997) ;
la cérivastatine (1998), retirée du marché en 2001 à cause de ses effets secondaires graves (nombre élevé de cas de rhabdomyolyse avec insuffisance rénale aiguë et décès), en particulier en association avec des fibrates ;
la fluvastatine (1994) ;
la lovastatine, la plus ancienne (1987), désormais quasiment obsolète et tirée de la levure de riz rouge ;
la mevastatine (années 1970) ;
la pitavastatine (1987) ;
la pravastatine (1991) ;
la rosuvastatine (2003) ;
la simvastatine (1988).

Utilisation Ces molécules sont efficace

Source officielle

https://fr.wikipedia.org/wiki/Statine

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Chargement

Transcriptional and post-transcriptional regulation of endothelin-1 gene by shear stress

Rafaela Fernandes Da Silva, Paolo Silacci, Nikolaos Stergiopulos

Objective Plaque-prone areas are exposed to a particular hemodynamic environment characterized by a low mean shear stress value and a cyclic reversal flow. This mechanical environment, also termed oscillatory shear stress (OSS), induces the expression of several pro-atherogenic genes in the endothelial cells including the preproendothelin-1 (ppET-1) gene. The present paper investigates the molecular mechanisms of this induction. Methods and results Several deletional mutants of ppET-1 gene promoter were cloned upstream of a luciferase gene and transiently transfected in bovine arterial endothelial cells that were further exposed to plaque-prone hemodynamics. After 24 h of flow exposure, analysis of the transfected cells showed that a proximal promoter of 156 base pairs length retained OSS responsiveness. Mutation of an activator protein-1 (AP-1) binding site present in this minimal promoter completely abolished its activation by OSS. Consistently, electrophoresis mobility shift assay revealed a sustained activation of AP-1 transcription factor in endothelial cells exposed to OSS. In addition to the transcriptional activation, we demonstrated that OSS also induces a stabilization of ppET-1 mRNA through the 3′-untranslated region (3′-UTR) of this gene. Fluvastatin, a drug known to improve endothelial function, was shown to prevent OSS up-regulation of the ppET-1 gene expression. Under this flow condition, fluvastatin affects ppET-1 gene expression via inhibition of its promoter activity without affecting ppET-1 mRNA stability. Conclusions The present study demonstrate that plaque-prone hemodynamic induces ppET-1 gene expression by both transcriptional and post-transcriptional mechanisms via an activation of AP-1 transcriptional factor and stabilization of mRNA. The transcriptional up-regulation of ppET-1 was shown to be fluvastatin sensitive.

2008

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3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-III and lipoprotein lipase

Johan Auwerx, Kristina Schoonjans

Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.

1999

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OBJECTIVE: Besides its predictive role in determining cardiovascular risk, C-reactive protein (CRP) may exert direct proatherogenic effects through proinflammatory properties. CRP is mainly produced by hepatocytes in response to interleukin-6 (IL-6) and is then released into the systemic circulation. 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors, or statins, significantly reduce cardiovascular events and mortality in patients with or without coronary artery disease and reduce plasma CRP levels in humans. However, the mechanism by which statins reduce plasma CRP levels remains unknown. METHODS AND RESULTS: In this study, we report that statins limit both protein and RNA levels of IL-6-induced CRP in human hepatocytes. These effects are reversed by l-mevalonate and mimicked by an inhibitor of the geranylgeranyltransferase. IL-6-induced CRP production requires the binding of IL-6 to its cognate receptors, which results in activation and phosphorylation of the transcription factor STAT3. We provide evidence that statins reduce this IL-6-induced phosphorylation of STAT3 in hepatocytes. CONCLUSIONS: These results demonstrate that statins reduce IL-6-induced CRP production directly in hepatocytes via inhibition of protein geranylgeranylation. We further show that statins act via inhibition of STAT3 phosphorylation. These findings furnish new evidence for direct antiinflammatory properties of statins and provide new mechanistic insight into their clinical benefits.

2005

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Transcriptional and post-transcriptional regulation of endothelin-1 gene by shear stress

Rafaela Fernandes Da Silva, Paolo Silacci, Nikolaos Stergiopulos

2008