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C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions.
Zhou, Alex-Xianghua; Wang, Xiaobo; Lin, Chyuan Sheng; Han, Jaeseok; Yong, Jing; Nadolski, Marissa J; Borén, Jan; Kaufman, Randal J; Tabas, Ira.
Afiliação
  • Zhou AX; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Wang X; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Lin CS; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Han J; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Yong J; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Nadolski MJ; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Borén J; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Kaufman RJ; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
  • Tabas I; From the Departments of Medicine (A.-X.Z., X.W., M.J.N., I.T.), Pathology and Cell Biology (C.S.L., I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg and Sahlgrenska U
Circ Res ; 116(11): 1736-43, 2015 May 22.
Article em En | MEDLINE | ID: mdl-25872946
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 SM22α(+) VSMCs in atherosclerosis. METHODS AND

RESULTS:

Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22α-CreKI(+) backgrounds. SM22α-CreKI causes deletion of floxed genes in adult SMCs. After 12 weeks of Western-type diet feeding, the content of α-actin-positive cells in aortic root lesions was decreased in Chop(fl/fl)SM22α-CreKI(+)Apoe(-/-) versus control Chop(fl/fl)Apoe(-/-) mice, and aortic explant-derived VSMCs from the VSMC-CHOP-deficient mice displayed reduced proliferation. Krüppel-like factor 4 (KLF4), a key suppressor of VSMC proliferation, was increased in lesions and aortic VSMCs from Chop(fl/fl)SM22α-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 SM22α-CHOP-deficient mice imply that CHOP expression in SM22α(+) 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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Miócitos de Músculo Liso / Proliferação de Células / Aterosclerose / Fator de Transcrição CHOP Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Miócitos de Músculo Liso / Proliferação de Células / Aterosclerose / Fator de Transcrição CHOP Idioma: En Ano de publicação: 2015 Tipo de documento: Article