Alex-Xianghua Zhou1, Xiaobo Wang2, Chyuan Sheng Lin1, Jaeseok Han1, Jing Yong1, Marissa J Nadolski1, Jan Borén1, Randal J Kaufman1, Ira Tabas2. 1. 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.). 2. 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.
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.
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-deficientmice 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-deficientVSMCs 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-deficientmice 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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