title: Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses.
abstract: BACKGROUND
  The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions.
  
  
  RESULTS
  We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury-induced neointimal formation was markedly inhibited in CHOP(-/-) mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation-related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E(-/-) mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation-related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress-induced upregulation of these proteins.
  
  
  CONCLUSIONS
  In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.
authors.affiliation: Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Junhong
authors.initials: J
authors.lastname: Gao
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Masataka
authors.initials: M
authors.lastname: Mori
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D013312:Stress, Physiological / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism*; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D016207:Cytokines; C497250:Ddit3 protein, mouse; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP