RÉSUMÉ
OBJECTIVE: The purpose of this study was to investigate the ability of high-density lipoproteins (HDLs) to upregulate genes with the potential to protect against inflammation in endothelial cells. METHODS AND RESULTS: Human coronary artery endothelial cells (HCAECs) were exposed to reconstituted HDLs (rHDLs) for 16 hours before being activated with tumor necrosis factor-alpha (TNF-alpha) for 5 hours. rHDLs decreased vascular cell adhesion molecule-1 (VCAM-1) promoter activity by 75% (P<0.05), via the nuclear factor-kappa B (NF-kappaB) binding site. rHDLs suppressed the canonical NF-kappaB pathway and decreased many NF-kappaB target genes. Suppression of NF-kappaB and VCAM-1 expression by rHDLs or native HDLs was dependent on an increase in 3beta-hydroxysteroid-Delta 24 reductase (DHCR24) levels (P<0.05). The effect of HDLs on DHCR24 is dependent on SR-BI but not ABCAI or ABCGI. Silencing DHCR24 expression increased NF-kappaB (1.2-fold, P<0.05), VCAM-1 (30-fold, P<0.05), and NF-kappaB p50 (4-fold, P<0.05) and p65 subunits (150-fold, P<0.05). TNF-alpha activation of siDHCR24-treated cells increased expression of VCAM-1 (550-fold, P<0.001) and NF-kappaB (9-fold, P<0.001) that could no longer be suppressed by rHDLs. CONCLUSIONS: Results suggest that antiinflammatory effects of rHDLs are mediated partly through an upregulation of DHCR24. These findings raise the possibility of considering DHCR24 as a target for therapeutic modulation.
Sujet(s)
Apolipoprotéine A-I/métabolisme , Artérite/prévention et contrôle , Athérosclérose/prévention et contrôle , Cellules endothéliales/enzymologie , Lipoprotéines HDL/métabolisme , Protéines de tissu nerveux/métabolisme , Oxidoreductases acting on CH-CH group donors/métabolisme , Animaux , Apolipoprotéine A-I/administration et posologie , Artérite/enzymologie , Artérite/étiologie , Artérite/génétique , Athérosclérose/enzymologie , Athérosclérose/étiologie , Athérosclérose/génétique , Cellules cultivées , Cholestérol alimentaire , Modèles animaux de maladie humaine , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes , Humains , I-kappa B Kinase/métabolisme , Protéines I-kappa B/métabolisme , Perfusions veineuses , Lipoprotéines HDL/administration et posologie , Inhibiteur alpha de NF-KappaB , Facteur de transcription NF-kappa B/métabolisme , Protéines de tissu nerveux/génétique , Oxidoreductases acting on CH-CH group donors/génétique , Régions promotrices (génétique) , Interférence par ARN , Petit ARN interférent/métabolisme , Lapins , Transfection , Facteur de nécrose tumorale alpha/métabolisme , Molécule-1 d'adhérence des cellules vasculaires/métabolismeRÉSUMÉ
Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie.
