Modulateurs du métabolisme du cholestérol et avenir du traitement de l’athérosclérose Cholesterol metabolism modulators in future drug therapy for atherosclerosis

Résumé

L’athérosclérose est la cause majeure des maladies cardiovasculaires et de leurs complications cliniques (accident cérébrovasculaire, infarctus du myocarde). Dans le monde, plus de 16 millions de personnes décèdent chaque année de ces maladies, ce qui représente près d’un tiers de tous les décès. Dans les pays industrialisés, l’athérosclérose, responsable d’environ 50 % des décès, est la première cause de mortalité. Les traitements actuels de cette maladie visent à en maîtriser les facteurs de risque, dont l’un des principaux est le taux élevé de cholestérol plasmatique. Les médicaments les plus efficaces contre l’athérosclérose sont hypocholestérolémiants et appartiennent à la classe des statines. Cependant, les statines diminuent la mortalité due aux maladies cardiovasculaires chez seulement un tiers des patients. De nouveaux produits, susceptibles de diminuer la cholestérolémie ou de ralentir la formation des lésions au niveau de la paroi vasculaire, devraient être développés.

Summary

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).