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C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions

Artikel i vetenskaplig tidskrift
Författare Alex-Xianghua Zhou
X. B. Wang
C. S. Lin
J. Han
J. Yong
M. J. Nadolski
Jan Borén
R. J. Kaufman
I. Tabas
Publicerad i Circulation Research
Volym 116
Nummer/häfte 11
Sidor 1736-+
ISSN 0009-7330
Publiceringsår 2015
Publicerad vid Wallenberglaboratoriet
Sidor 1736-+
Språk en
Länkar dx.doi.org/10.1161/circresaha.116.3...
Ämnesord activating transcription factor 4, atherosclerosis, transcription factor CHOP, unfolded protein, ENDOPLASMIC-RETICULUM STRESS, GENE-EXPRESSION, MECHANISMS, APOPTOSIS, PLAQUES, MACROPHAGES, PROGRESSION, ACTIVATION, INITIATION, RESPONSES, Cardiac & Cardiovascular Systems, Hematology, Peripheral Vascular, Disease
Ämneskategorier Cell- och molekylärbiologi

Sammanfattning

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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