Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells

• Published in: Circulation (New York, N.Y.) Vol. 106; no. 23; pp. 2888 - 2893
• Main Authors: SCHÖNBECK, Uwe, GERDES, Norbert, VARO, Nerea, REYNOLDS, Rebecca S, HORTON, Daniel B, BAVENDIEK, Udo, ROBBIE, Linda, GANZ, Peter, KINLAY, Scott, LIBBY, Peter
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03.12.2002; American Heart Association, Inc
• Subjects: Animals; Atorvastatin; Biological and medical sciences; Blood Coagulation - genetics; CD40 Antigens - genetics; CD40 Antigens - metabolism; CD40 Ligand - blood; CD40 Ligand - genetics; CD40 Ligand - metabolism; Cells, Cultured; Cohort Studies; Coronary Stenosis - blood; Coronary Stenosis - drug therapy; Cytokines - pharmacology; Dose-Response Relationship, Drug; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Female; General and cellular metabolism. Vitamins; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipoproteins, LDL - pharmacology; Male; Medical sciences; Mice; Middle Aged; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Phagocytes - cytology; Phagocytes - drug effects; Phagocytes - metabolism; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyrroles - pharmacology; RNA, Messenger - metabolism; Simvastatin - pharmacology; Human; Cell culture; Endothelial cell; Enzyme; Hydroxymethylglutaryl-CoA synthase; Enzyme inhibitor; Cardiovascular disease; Smooth muscle; Lyases; Inflammation; Biological activity; Oxo-acid-lyases; Vascular disease; Lipoprotein LDL; Carbon-carbon lyases; Blood vessel; statins; Atherosclerosis; Oxidation; Antilipemic agent
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000043029.52803.7B

Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo. Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3+/-3.1 ng/mL [n=11] versus 13.1+/-2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis. OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.