HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering?
Atherosclerosis has many features of a chronic inflammatory disease. Atherosclerotic lesions contain inflammatory cells. Systemic markers of inflammation, such as white blood cells, C-reactive protein, serum amyloid A, interleukin-6, and soluble adhesion molecules are predictive of future cardiovascular events. Atherogenic lipoprotein particles, in particular modified low-density lipoproteins (LDL), elicit pro-inflammatory responses of cellular elements of the vessel wall, including endothelial dysfunction and activation of monocyte-derived macrophages. High-density lipoproteins (HDL) oppose these effects by inhibiting the oxidation of LDL, and by down-regulating the expression of adhesion molecules and selectins. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has proven the most successful strategy to reduce the concentration of LDL in the circulation. These compounds lower LDL cholesterol by inhibiting the mevalonate pathway in the liver. Prospective clinical trials have convincingly demonstrated that HMG-CoA reductase inhibitors can effectively lower the incidence of cardiovascular events in primary and secondary prevention. Post hoc analyses of these trials suggest that the clinical benefit brought about by statins may not entirely be due to their effect on the levels of circulating lipoproteins. In vitro observations of anti-inflammatory actions of statins on vascular cells may contribute to explain effects beyond lipid lowering. It is, however, not clear whether these findings are relevant to the in vivo situation. Further investigation is now necessary in order to determine the relative significance of cholesterol lowering and of ancillary effects on the net clinical benefit of statin treatment.
März
Winfried
W
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl Franzens-University, Graz, Austria. winfried.maerz@klinikum-graz.at
Köenig
Wolfgang
W
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000150:complications / Q000517:prevention & control*; D004195:Disease Models, Animal; D000882:Haplorhini; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy*; D066298:In Vitro Techniques; D051379:Mice; D011817:Rabbits; D051381:Rats; D014657:Vasculitis / Q000150:complications / Q000188:drug therapy*
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors