Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses

Junhong Gao, Yasushi Ishigaki, Tetsuya Yamada, Keiichi Kondo, Suguru Yamaguchi, Junta Imai, Kenji Uno, Yutaka Hasegawa, Shojiro Sawada, Hisamitsu Ishihara, Seiichi Oyadomari, Masataka Mori, Yoshitomo Oka, Hideki Katagiri

Research output: Contribution to journalArticle

40 Citations (Scopus)

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. Methods and 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.

Original languageEnglish
Pages (from-to)830-839
Number of pages10
JournalCirculation
Volume124
Issue number7
DOIs
Publication statusPublished - 2011 Aug 16

Keywords

  • atherosclerosis
  • inflammation
  • remodeling
  • stress physiological
  • transcription factor CHOP

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Gao, J., Ishigaki, Y., Yamada, T., Kondo, K., Yamaguchi, S., Imai, J., Uno, K., Hasegawa, Y., Sawada, S., Ishihara, H., Oyadomari, S., Mori, M., Oka, Y., & Katagiri, H. (2011). Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses. Circulation, 124(7), 830-839. https://doi.org/10.1161/CIRCULATIONAHA.110.014050