Pitavastatin decreases the expression of endothelial lipase both in vitro and in vivo

• Published in: Cardiovascular research 2010-07, Vol.87 (2), p.385-393
• Main Authors: Kojima, Yoko, Ishida, Tatsuro, Sun, Li, Yasuda, Tomoyuki, Toh, Ryuji, Rikitake, Yoshiyuki, Fukuda, Akira, Kume, Noriaki, Koshiyama, Hiroyuki, Taniguchi, Ataru, Hirata, Ken-ichi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Cardiology. Vascular system; Cells, Cultured; Cholesterol, HDL - blood; Dose-Response Relationship, Drug; Down-Regulation; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; HDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Hypercholesterolemia - enzymology; Lipase - blood; Lipase - genetics; Lipase - metabolism; Lipases; Lipids; Lipoproteins; Male; Medical sciences; Mevalonic Acid - metabolism; Mice; Mice, Inbred C57BL; Middle Aged; Polyisoprenyl Phosphates - metabolism; Prospective Studies; Protein Kinase Inhibitors - pharmacology; Protein Prenylation; Quinolines - therapeutic use; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - metabolism; Statin; Time Factors; Transfection; Treatment Outcome
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp419

Aims In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated. Methods and results The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia. Conclusion These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.