C/EBP-Homologous protein (CHOP) in vascular smooth muscle cells regulates their proliferation in aortic explants and atherosclerotic lesions

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: 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 weeks of Western-type diet feeding, The content of α-actin-positive cells in aortic root lesions was decreased in Chopfl/flSM22α-CreKI+Apoe-/- versus 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 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.