Les statines : nouvelles propriétés

doi:10.2515/therapie:2003003

Therapies

Volume 58, Issue 1, January–February 2003, Pages 15-21

https://doi.org/10.2515/therapie:2003003 Get rights and content

Résumé

La comparaison des essais cliniques des statines avec ceux utilisant la dérivation iléale ou les résines suggère que la prévention des événements cardiovasculaires sous statines est principalement due à la diminution de la cholestérolémie. Celle-ci a de multiples conséquences physiologiques, principalement la stabilisation des plaques d’athérosclérose qui deviennent moins inflammatoires, le ralentissement de la progression des lésions et l’amélioration de la fonction endothéliale telle qu’elle est mise en évidence par la vasodilatation en réponse à l’acétylcholine ou l’hyperhémie. Cependant, en plus de la synthèse de cholestérol, les statines inhibent d’autres voies métaboliques, en particulier l’isoprénylation des protéines Rho et Ras, avec pour conséquences potentielles la diminution de la production de NO par la cellule endothéliale, l’activation des PPARα, la stimulation de l’apoptose des cellules musculaires lisses, l’inhibition de l’adhésion des monocytes sur l’endothélium etc… Ces fonctions ont été principalement mises en évidence, in vitro ou chez l’animal, en utilisant des concentrations de statines souvent supra-thérapeutiques. Il reste à démontrer que chez l’homme, à des doses thérapeutiques, le blocage de l’isoprénylation joue réellement un rôle favorable.

Abstract

The comparison of major statin trials with trials using either cholestyramine or ileal bypass has suggested that the reduction in coronary heart disease events for those patients receiving statin therapy largely result from their low density lipoprotein (LDL)-cholesterol lowering action. LDL-cholesterol lowering has several physiological consequences, including plaque stabilisation with a decrease in the inflammatory process, slowing of plaque progression, and improvement of endothelial function, as evidenced by the measurement of endothelial-dependent vasorelaxation in response to hyperhaemia or acetylcholine infusion. Statins lower C-reactive protein without any consistent effect on the other inflammation acute phase proteins. The cause and consequences of this effect are still debated.

In order to explain why some statins can prevent coronary events within a few months, a direct effect of this therapy on thrombosis has also been advocated; however, the evaluation of statin antithrombotic effects in humans has produced conflicting results. By inhibiting L-mevalonic acid synthesis, statins also prevent the farnelysation of small-GTP binding proteins such as Rho and Ras. In vitro, and in animal models, the inhibition of Rho with statins results in a decrease in endothelial nitric oxide production, an inhibition of leucocyte adhesion on endothelium, decrease in PPARα activation and high density lipoprotein (HDL) production by the hepatocyte, decrease in Ca²⁺ stores in vascular smooth cells, and a stimulation of vascular smooth muscle cell apoptosis. However, most of these effects were obtained with high statin concentrations. Further evidence is needed before a full assessment of the clinical importance of isoprenylation blockage with therapeutic concentrations of statins in humans can be made.

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Cited by (13)

Effects of atorvastatin in suppressing pulmonary vascular remodeling in rats with chronic obstructive pulmonary disease
2023, Clinics
To investigate the effects of atorvastatin calcium on pulmonary vascular remodeling, the authors explored the regulatory mechanism of Histone Deacetylation Enzyme-2 (HDAC2) in rats with Chronic Obstructive Pulmonary Disease (COPD), and provided a new direction for drug treatment in the progression of vascular remodeling.
Eighteen female SD rats were randomly divided into control (Group S1), COPD (Group S2), and atorvastatin calcium + COPD (Group S3) groups. A COPD rat model was established by passive smoking and intratracheal injection of Lipopolysaccharide (LPS). Haematoxylin and eosin staining and Victoria Blue + Van Gibson staining were used to observe pathological changes in the lung tissue. The pulmonary vascular inflammation score was calculated, and the degree of pulmonary vascular remodeling was evaluated. The ratio of Muscular Arteries in lung tissue (MA%), the ratio of the vessel Wall Area to the vessel total area (WA%), and the ratio of the vessel Wall Thickness to the vascular outer diameter (WT%) were measured using imaging software. The expression of HDAC2 was measured using western blotting, ELISA (Enzyme-Linked Immunosorbent Assay), and qPCR (Real-time PCR).
Compared with the control group, the degree of pulmonary vascular inflammation and pulmonary vascular remodeling increased in rats with COPD. The WT%, WA%, and lung inflammation scores increased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissue decreased, and the level of Vascular Endothelial Growth Factor (VEGF) in the lung tissues increased (p < 0.05). Compared with the COPD group, the lung tissues from rats in the atorvastatin group had fewer inflammatory cells, and the vascular pathological changes were significantly relieved. The WT%, WA%, and lung inflammation scores decreased significantly; the expression of HDAC2 and HDAC2mRNA in the serum and lung tissues increased, and the level of VEGF in the lung tissues decreased (p < 0.05).
The present study revealed that atorvastatin calcium could regulate the contents and expression of HDAC2 in serum and lung tissues and inhibit the production of VEGF, thereby regulating pulmonary vascular remodeling in a rat model with COPD.
Short-term clinical effects of periprocedural statin therapy
2013, Presse Medicale
In high-risk patients, long-term statin therapy prevents cardiovascular events. Short-term clinical benefit of statin therapy has been recently evaluated by randomized clinical trials in the setting of vascular surgery, coronary bypass surgery and percutaneous coronary interventions. According to the trial scheme, statin therapy was started either few weeks or few hours before the intervention.
In the field of vascular surgery, the clinical benefit of preprocedure statin administration has been supported by DECREASE III trial. Fluvastatin significantly decreased the incidence of periprocedural myocardial ischemia as defined by ECG changes or troponin elevation. However, this study has methodological flaws, including primary endpoint modification during the trial and the lack of clinical relevance of this endpoint.
The administration of statins before a coronary bypass could reduce the occurrence of postoperative atrial fibrillation, according to 4 randomized trials. This finding is discordant with the result of a recent meta-analysis of long-term published and unpublished long-term trials that showed no significant beneficial effects of statins on atrial fibrillation.
Several trials have evaluated the usefulness of statin pretreatment before PCI. Most of them have found that statin pretreatment prevents periprocedural myocardial infarctions or major cardiac events. However, most of these events were isolated enzymatic elevations. Moreover, myocardial infarction definition was at odds with the recommendations in some of these trials.
A recent meta-analysis of these trials has found that statin pretreatment leads to a 44% reduction in the incidence of major cardiac events at 30 days. The magnitude of this decrease is not consistent with the results of previous long-term trials evaluating statins after acute coronary syndromes.
Current evidence does not strongly support short-term clinical benefit of pre-procedural statin administration.
Chez les patients à haut risque vasculaire, les statines préviennent les événements cardiovasculaires à long terme. Leur effet à court terme a été récemment évalué par des essais randomisés chez des patients bénéficiant d’une chirurgie vasculaire, d’un pontage aortocoronaire ou d’une intervention coronaire percutanée. La statine était initiée selon les cas quelques semaines à quelques heures avant l’intervention.
Dans le domaine de la chirurgie vasculaire, l’étude DECREASE III a suggéré que la fluvastatine débutée avant la chirurgie diminue l’incidence des ischémies myocardiques périopératoires. Cependant, cette étude contient diverses difficultés méthodologiques, en particulier la modification du critère principal en cours d’essai.
Initiées avant un pontage aortocoronaire, les statines préviendraient la fibrillation auriculaire pendant la phase hospitalière, d’après 4 essais randomisés. Ce résultat est discordant avec celui d’une méta-analyse récente d’essais publiés et non publiés, évaluant des statines au long cours, qui ne montre pas de prévention de la fibrillation auriculaire.
L’administration d’une statine avant une intervention coronaire percutanée a été évalué par de nombreux essais randomisés. Dans leur grande majorité, ces essais ont trouvé un effet significatif de la statine pour prévenir la nécrose myocardique et/ou les événements cardiaques majeurs post-procédure. Cependant, la plus grande partie des événements évités étaient des nécroses purement biologiques. De plus, la définition de la nécrose n’était pas toujours conforme aux recommandations.
La méta-analyse de ces essais a montré que les statines diminuent de près de moitié l’incidence des événements cardiaques majeurs post-procédure, ce qui n’est pas cohérent avec les résultats de grands essais évaluant à plus long terme une statine dans les suites d’un syndrome coronaire aigu.
L’ensemble de ces essais ne paraît pas suffisant pour établir le bénéfice à court terme de la prescription d’une statine avant une intervention.
Simvastatin inhibits cell cycle progression in glucose-stimulated proliferation of aortic vascular smooth muscle cells by up-regulating cyclin dependent kinase inhibitors and p53
2008, Pharmacological Research
Simvastatin was reported to attenuate platelet-derived growth factor (PDGF)-induced vascular smooth muscle proliferation by up-regulation of cyclin dependent kinase (CDK) inhibitor p27, but had no effect on p16, p21, p53 expression. We investigate the mechanisms by which simvastatin inhibits vascular smooth muscle cell (VSMC) growth in high glucose conditions to mimic diabetes. Simvastatin was added to A7r5 cells cultured in high glucose (25 mM) medium, mimicking diabetes. We used an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cell viability; flow cytometric analysis for cell counts distribution in the cell cycle; and Western blot, immunoblotting, and immunoprecipitation analyses to evaluate the effects of simvastatin on CDK activity and cell cycle regulatory proteins. Cell counts were significantly increased in G0/G1 phase and significantly decreased in S and G2/M phases. In our study, low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. In conclusion, simvastatin inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. We propose that statins may be used more extensively in diabetic patients regardless of lipid status for preventing atherosclerosis and restenosis after PCI.
Effect of simvastatin and fenofibrate on endothelium in Type 2 diabetes
2004, European Journal of Pharmacology
Statins and fibrates influence endothelial activity and consequently atherogenesis but the mechanisms are not well understood. Twenty Type 2 diabetic patients with dyslipidemia were treated 3 months with simvastatin (20 mg daily) and then 3 months with fenofibrate (200 mg daily) with 2 months of wash-out between the two treatments. Laboratory parameters of oxidative stress, fibrinolysis and endothelial function were evaluated before and at the end of each treatment period. The significant decrease in serum total and LDL-cholesterol concentrations (P<0.0001) caused by simvastatin was associated with an increase in serum N-acetyl-β-glucosaminidase activity (P<0.001), ascorbic acid (P<0.001), plasminogen activator inhibitor (PAI-1) (P<0.01), vonWillebrand factor (P<0.05), E-selectin (P<0.01) and vascular endothelial growth factor (P<0.05) concentrations and with a decrease in plasma glutathione (P<0.01) levels. Fenofibrate caused a significant decrease in serum triglyceride concentration (P<0.0001) associated with a decrease in plasma malondialdehyde (P<0.001) and an increase in plasma PAI-1 (P<0.05) and P-selectin (P<0.05) concentrations. We conclude that simvastatin and fenofibrate interact, by different mechanisms, with oxidative stress, a key factor in the modification of fibrinolysis and endothelial function in Type 2 diabetes.
Atorvastatin mitigates memory deficits and brain monocyte infiltration in chronic hypercholesterolemia
2023, Aging
Effects of statins and xuezhikang on the expression of secretory phospholipase A2, group IIa in rat vascular smooth muscle cells
2017, International Heart Journal

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PharmacologieLes statines : nouvelles propriétésPleiotropic Effects of Statins

Résumé

Abstract

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Pharmacologie
Les statines : nouvelles propriétésPleiotropic Effects of Statins