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

Journal article
Authors Alex-Xianghua Zhou
X. B. Wang
C. S. Lin
J. Han
J. Yong
M. J. Nadolski
Jan Borén
R. J. Kaufman
I. Tabas
Published in Circulation Research
Volume 116
Issue 11
Pages 1736-+
ISSN 0009-7330
Publication year 2015
Published at Wallenberg Laboratory
Pages 1736-+
Language en
Links dx.doi.org/10.1161/circresaha.116.3...
Keywords 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
Subject categories Cell and Molecular Biology

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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