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Abstract
Osteopontin (OPN) is known as an active player in the progression of vascular remodeling
diseases, however, the precise role in the proliferation of vascular smooth muscle
cells (VSMC) is unclear. Thus, this study investigated the role of OPN in VSMC proliferation
induced by 4-hydroxynonenal (HNE), and identified the intracellular signaling pathways
involved in 4-HNE-induced OPN production. In VSMC primary cultured from rat thoracic
aorta as well as in VSMC in the media of aorta, HNE enhanced OPN expression in concentration-dependent
manners. Both the proliferation of cultured VSMC and PCNA positive cells in aortic
tissues were also increased by HNE, which were attenuated in OPN-deficient cells and
aortic tissues isolated from OPN-deficient mice, indicating a pivotal role of OPN
in HNE-induced VSMC proliferation. In the promoter assay, HNE increased OPN promoter
activity, which was attenuated when the regions harboring AP-1 and C/EBPβ binding
sites were mutated. The increased bindings of AP-1 and C/EBPβ to the OPN promoter
were also demonstrated by ChIP analysis. In addition, the increases in both OPN expression
and the activities of AP-1 and C/EBPβ by HNE were attenuated by AG1478, an EGFR antagonist.
Based on these results, it was suggested that HNE induced OPN expression in VSMC via
signaling pathways involving AP-1 and C/EBPβ, leading to increases in VSMC proliferation
and subsequent vascular remodeling.