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) ) is a risk factor for atherosclerosis, restenosis after angioplasty, ischemic heart disease, and cerebral stroke. [1][2][3][4][5][6] Lp(a) consists of LDL with an additional protein component, apolipoprotein (a), a homologue of plasminogen. 7 Lp(a) and apolipoprotein (a) have been thought to enhance proliferation of human vascular smooth muscle cells (VSMC). 8 -10 On the other hand, Lp(a) has been postulated to bind to endothelial cells and macrophages and to extracellular components such as fibrin and inhibit cell-associated plasminogen activation. 11,12 Recently, numerous types of stress such as oxidation have been suggested to be involved in the development of atherosclerosis. For example, oxidized LDL caused by oxidative stress such as that in hypertension and diabetes but not native LDL has been postulated to be related to atherosclerosis. 13 Other lipoproteins such as Lp(a) could also be modified by oxidation. Expectedly, oxidative modification enhances the inhibitory effect of Lp(a) on plasminogen binding to U937 cell surfaces. 14 These findings suggest that the oxidative form of Lp(a) rather than native Lp(a) may attenuate fibrinolytic activity through reduction of plasminogen activation. We discovered a monoclonal antibody that recognizes an epitope of modified Lp(a) as a result of oxidation treatment. 15 Since this epitope is hidden on the native Lp(a) molecule, we successfully developed a new ELISA system by using this antibody, which can distinguish native and oxidized Lp(a). With the use of this antibody, the presence of oxidized Lp (a) could be detected in human serum and human atherosclerotic lesions. 15 However, the exact role of oxidized Lp(a) is still largely unknown. This study demonstrates the potent mitogenic activity of oxidized Lp(a) compared with native Lp(a) in the growth of human aort...