3'UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modified anti-platelet activity of atorvastatin in hypercholesterolemic subjects.
Oxidized-low density lipoproteins (ox-LDL) and the specific receptor LOX-1 are involved in atherogenesis and atherothrombosis. LOX-1 downregulation is associated with the anti-platelet action of atorvastatin. 3'UTR/T LOX-1 polymorphism has been associated with increased risk of coronary artery disease. This study was planned to determine whether LOX-1 genetic variations could affect anti-platelet action of atorvastatin. We studied by platelet P-selectin (P-sel), CD36 and LOX-1 expression (cytofluorimetric detection) whether differences in cellular activation could be suitable in 109 3'UTR/T carriers out of 201 hypercholesterolemic subjects treated with atorvastatin 20mg/day. Hyperactivated platelets (P-sel in resting cells and % variation upon thrombin activation, p<0.001) were detected at baseline in patients without significant differences between T or C carriers. P-sel and platelet-associated ox-LDL, were significantly decreased (all p<0.001) in C carriers after one week of treatment before LDL reduction. In 3'UTR/T carriers P-sel was reduced (p<0.01) after 6 weeks of treatment according to LDL and ox-LDL reduction. In 3'UTR/T carriers atorvastatin reduced platelet activity by LDL and ox-LDL lowering and not by rapid CD36 and LOX-1 downregulation as in C carriers. Such data suggest that in T carriers LDL lowering is needed to achieve anti-platelet action.
Puccetti
Luca
L
Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Center for Atherosclerosis Research, University of Siena, Siena, Italy. puccetti@unisi.it
Pasqui
Anna Laura
AL
Pastorelli
Marcello
M
Ciani
Federica
F
Palazzuoli
Alberto
A
Gioffrè
Walter
W
Auteri
Alberto
A
Bruni
Fulvio
F
D000328:Adult; D000483:Alleles; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D001792:Blood Platelets / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D005838:Genotype; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000627:therapeutic use*; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; C495137:OLR1 protein, human; D019007:P-Selectin; D011758:Pyrroles; D051127:Scavenger Receptors, Class E; D002956:Citrulline; D004247:DNA; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase