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

ABSTRACT: 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.To investigate the role of CHOP in SM22?(+) VSMCs in atherosclerosis.Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22?-CreKI(+) backgrounds. SM22?-CreKI causes deletion of floxed genes in adult SMCs. After 12 weeks of Western-type diet feeding, the content of ?-actin-positive cells in aortic root lesions was decreased in Chop(fl/fl)SM22?-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)SM22?-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.These findings in SM22?-CHOP-deficient mice imply that CHOP expression in SM22?(+) VSMCs promotes cell proliferation by downregulating KLF4. The mechanisms involve newly discovered roles of CHOP in the transcriptional and post-translational regulation of KLF4.

SUBMITTER: Zhou AX

PROVIDER: S-EPMC4441876 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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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 AX Wang Xiaobo X Lin Chyuan Sheng CS Han Jaeseok J Yong Jing J Nadolski Marissa J MJ Borén Jan J Kaufman Randal J RJ Tabas Ira I

Circulation research 20150414 11

<h4>Rationale</h4>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.<h4>Objective</h4>To investigate the role of CHOP in SM22α(+) VSMCs in atherosclerosis.<h4>Methods and results</h4>Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22α-CreKI(+) b ...[more]

PMID: 25872946

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Project description:Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (? 2 ?m by 0.5 ?m), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.

Dataset Information

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

Publications

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

Similar Datasets

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