title: Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification.
abstract: Our previous work reported that endoplasmic reticulum stress (ERS)-mediated apoptosis was activated during vascular calcification (VC). Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis. However, whether ATF4 is involved in ERS-mediated apoptosis contributing to VC remains unclear. In the present study, in vivo VC was induced in rats by administering vitamin D3 plus nicotine. Vascular smooth muscle cell (VSMC) calcification in vitro was induced by incubation in calcifying media containing β-glycerophosphate and CaCl2. ERS inhibitors taurine or 4-phenylbutyric acid attenuated ERS and VSMC apoptosis in calcified rat arteries, reduced calcification and retarded the VSMC contractile phenotype transforming into an osteoblast-like phenotype in vivo. Inhibition of ERS retarded the VSMC phenotypic transition into an osteoblast-like cell phenotype and reduced VSMC calcification and apoptosis in vitro. Interestingly, ATF4 was activated in calcified aortas and calcified VSMCs in vitro. ATF4 knockdown attenuated ERS-induced apoptosis in calcified VSMCs. ATF4 deficiency blocked VSMC calcification and negatively regulated the osteoblast phenotypic transition of VSMCs in vitro. Our results demonstrate that ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to VC.
authors.affiliation: The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Duan
authors.forename: Jin-Rui
authors.initials: JR
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Bao-Hong
authors.initials: BH
authors.lastname: Zhang
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Teng
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Chao-Shu
authors.initials: CS
authors.lastname: Tang
authors.forename: Yong-Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D051701:Activating Transcription Factor 4