Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism.
The advanced atherosclerotic lesion is characterized by the formation of microscopic cholesterol crystals that contribute to mechanisms of inflammation and apoptotic cell death. These crystals develop from membrane cholesterol domains, a process that is accelerated under conditions of hyperlipidemia and oxidative stress. In this study, the comparative effects of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on oxidative stress-induced cholesterol domain formation were tested in model membranes containing physiologic levels of cholesterol using small angle x-ray diffraction approaches. In the absence of HMG-CoA reductase, only the atorvastatin active o-hydroxy metabolite (ATM) blocked membrane cholesterol domain formation as a function of oxidative stress. This effect of ATM is attributed to electron donation and proton stabilization mechanisms associated with its phenoxy group located in the membrane hydrocarbon core. ATM inhibited lipid peroxidation in human low density lipoprotein and phospholipid vesicles in a dose-dependent manner, unlike its parent and other statins (pravastatin, rosuvastatin, simvastatin). These findings indicate an atheroprotective effect of ATM on membrane lipid organization through a potent antioxidant mechanism.
Mason
R Preston
RP
Elucida Research, Beverly, Massachusetts 01915-0091, USA. rpmason@elucidaresearch.com
Walter
Mary F
MF
Day
Charles A
CA
Jacob
Robert F
RF
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D050197:Atherosclerosis / Q000503:physiopathology / Q000517:prevention & control; D000069059:Atorvastatin; D002462:Cell Membrane; D008078:Cholesterol, LDL / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias; D007249:Inflammation; D015227:Lipid Peroxidation; D008563:Membrane Lipids / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D011758:Pyrroles / Q000494:pharmacology*; D014961:X-Ray Diffraction
D000975:Antioxidants; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008563:Membrane Lipids; D011758:Pyrroles; D000069059:Atorvastatin