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 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 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 ChopSM22α-CreKIApoe versus control ChopApoe 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 ChopSM22α-CreKIApoe 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 4transcriptional 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.