title: Osteopontin plays a key role in vascular smooth muscle cell proliferation via EGFR-mediated activation of AP-1 and C/EBPβ pathways.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam 626-870, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam 626-870, Republic of Korea.
authors.forename: Seung Eun
authors.initials: SE
authors.lastname: Baek
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam 626-870, Republic of Korea.
authors.forename: Min A
authors.initials: MA
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea; Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam 626-870, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000447:Aldehydes; D022782:CCAAT-Enhancer-Binding Protein-beta; D018808:Transcription Factor AP-1; D053495:Osteopontin; C483803:Egfr protein, rat; D066246:ErbB Receptors; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal; EGF receptor; Osteopontin; Transcription factor; Vascular remodeling; Vascular smooth muscle cell