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: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. Kruppel-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 ...