title: Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells.
abstract: Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.
authors.affiliation: Department of Geriatric Medicine, Osaka University Medical School, Suita 565, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Komai
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Oishi
authors.forename: Sota
authors.initials: S
authors.lastname: Iguchi
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Minako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Ikunosuke
authors.initials: I
authors.lastname: Sakurabayashi
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D001011:Aorta / Q000166:cytology / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D017270:Lipoprotein(a) / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D017270:Lipoprotein(a); D008934:Mitogens; D020928:Mitogen-Activated Protein Kinases