C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions
- Authors
- Zhou, Alex-Xianghua; Wang, Xiaobo; Lin, Chyuan Sheng; Han, Jaeseok; Yong, Jing; Nadolski, Marissa J.; Boren, Jan; Kaufman, Randal J.; Tabas, Ira
- Issue Date
- 22-May-2015
- Publisher
- Lippincott Williams & Wilkins Ltd.
- Keywords
- activating transcription factor 4; atherosclerosis; transcription factor CHOP; unfolded protein response; vascular smooth muscle cells
- Citation
- Circulation Research, v.116, no.11, pp 1736 - +
- Journal Title
- Circulation Research
- Volume
- 116
- Number
- 11
- Start Page
- 1736
- End Page
- +
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/10641
- DOI
- 10.1161/CIRCRESAHA.116.305602
- ISSN
- 0009-7330
1524-4571
- Abstract
- Rationale: Myeloid-derived C/EBP-homologous protein (CHOP), an effector of the endoplasmic reticulum stress-induced unfolded protein response, promotes macrophage apoptosis in advanced atherosclerosis, but the role of CHOP in vascular smooth muscle cells (VSMCs) in atherosclerosis is not known. Objective: To investigate the role of CHOP in SM22 alpha(+) VSMCs in atherosclerosis. Methods and Results: Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22 alpha-CreKI(+) backgrounds. SM22 alpha-CreKI causes deletion of floxed genes in adult SMCs. After 12 weeks of Western-type diet feeding, the content of alpha-actin-positive cells in aortic root lesions was decreased in Chop(fl/fl)SM22 alpha-CreKI(+) Apoe(-/-) versus control Chop(fl/fl)Apoe(-/-) mice, and aortic explant-derived VSMCs from the VSMC-CHOP-deficient mice displayed reduced proliferation. Kruppel-like factor 4 (KLF4), a key suppressor of VSMC proliferation, was increased in lesions and aortic VSMCs from Chop(fl/fl)SM22 alpha-CreKI(+) Apoe(-/-) mice, and silencing Klf4 in CHOP-deficient VSMCs restored proliferation. CHOP deficiency in aortic VSMCs increased KLF4 through 2 mechanisms mediated by the endoplasmic reticulum stress effector activating transcription factor 4: transcriptional induction of Klf4 mRNA and decreased proteasomal degradation of KLF4 protein. Conclusions: These findings in SM22 alpha-CHOP-deficient mice imply that CHOP expression in SM22 alpha(+) VSMCs promotes cell proliferation by downregulating KLF4. The mechanisms involve newly discovered roles of CHOP in the transcriptional and post-translational regulation of KLF4.
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Collections - Graduate School > Department of Integrated Biomedical Science > 1. Journal Articles
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