title: C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions.
abstract: BACKGROUND
  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.
  
  
  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.
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Alex-Xianghua
authors: AX
authors: Zhou
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.). iat1@columbia.edu xw2279@columbia.edu.
authors: Xiaobo
authors: X
authors: Wang
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Chyuan Sheng
authors: CS
authors: Lin
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Jaeseok
authors: J
authors: Han
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Jing
authors: J
authors: Yong
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Marissa J
authors: MJ
authors: Nadolski
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Jan
authors: J
authors: Borén
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.).
authors: Randal J
authors: RJ
authors: Kaufman
authors: 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 University Hospital, Gothenburg, Sweden (A.-X.Z., J.B.); CVMD iMed Translational Science, AstraZeneca R and D, Mölndal, Sweden (A.-X.Z.); Soonchunhyang Institute of Med-Bio Science, Soonchunhyang University, Cheon-an, South Korea (J.H.); and Degenerative Disease Program, Sanford-Burnham Medical Research Institute, La Jolla, CA (J.H., J.Y., R.J.K.). iat1@columbia.edu xw2279@columbia.edu.
authors: Ira
authors: I
authors: Tabas
mesh_terms: D000199:Actins / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D015151:Immunoblotting; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D051742:Transcription Factor CHOP / Q000172:deficiency* / Q000235:genetics
chemical_list: D000199:Actins; D001057:Apolipoproteins E; C081452:Atf4 protein, mouse; C497250:Ddit3 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP
keywords: activating transcription factor 4; atherosclerosis; transcription factor CHOP; unfolded protein response; vascular smooth muscle cells