Influence of HMG-CoA Reductase Inhibitors on Leptin-Induced Endothelial Cell Proliferation, Migration, and Capillary-Like Tube Formation

Abstract

Objective: This study investigated the impact of the hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on the leptin-induced human umbilical vein endothelial (HUVE) cell proliferation, migration, and capillary-like tube formation. Methods: The HUVE cells were isolated and cultured, and stimulated with leptin, statins (cerivastatin, fluvastatin, simvastatin), mevalonate, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, or methyl-β-cyclodextrin. The endothelial cell proliferation was assessed using the Neubauer counting chamber. The migration of HUVE cells was examined with the planar migration assay. In vitro capillary sprouting was quantified by measuring the sprout length, number, and cumulative sprout length. Results: The HMG-CoA reductase inhibitors significantly reduced leptin-induced proliferation and migration, which was reversed by mevalonate. Further, the inhibitory effect of the statins on leptin-induced migration was shown to be modulated by the prenylation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Although stimulation with a leptin showed no significant effect, a marked increase in capillary-like tube formation was observed with a joint stimulation with HMG-CoA reductase inhibitors. Although statins caused inhibition of proliferation and migration, the same dose of the agents amplified the selective growth of capillary-like tube formation. Membranous cholesterol depletion by methyl-β-cyclodextrin showed a weaker effect compared with statins. Conclusion: Through modulation of prenylation, leptin-induced pro-atherosclerotic events including proliferation and migration were inhibited by HMG-CoA reductase inhibitors.

Keywords:

• atherosclerosis
• statins
• leptin
• FPP
• GGPP
• angiogenesis
• proliferation
• migration
• HUVE cells