C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions
Rationale: Myeloid-derived C/EBP-homologous protein (CHOP), an effector of the endoplasmic reticulum (ER) 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: Chopfl/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 wks of Western-type diet feeding, the content of α-actin-positive cells in aortic root lesions was decreased in Chopfl/flSM22α-CreKI+Apoe−/− vs. control Chopfl/flApoe−/− 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 Chopfl/flSM22α-CreKI+Apoe-/− mice, and silencing Klf4 in CHOP-deficient VSMCs restored proliferation. CHOP deficiency in aortic VSMCs increased KLF4 through two mechanisms mediated by the ER stress effector ATF4: 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 down-regulating KLF4. The mechanisms involve newly discovered roles of CHOP in the transcriptional and post-translational regulation of KLF4.
- ER stress
- Unfolded Protein Response
- C/EBP-homologous protein
- Krüppel-like factor 4
- activating transcription factor 4
- vascular smooth muscle
- cell signaling
- animal model cardiovascular disease
- Received November 8, 2014.
- Revision received April 8, 2015.
- Accepted April 13, 2015.