title: Low dose tunicamycin enhances atherosclerotic plaque stability by inducing autophagy.
abstract: After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3.0mg/kg) and lower (0.3mg/kg) doses of tunicamycin (TM), and plaque stability was evaluated. It was shown that lower TM-treated animals exhibited reduced plaque areas and necrotic cores as well as fibrous cap thickness accompanied by a lower percentage of infiltrates and foam cells than the sham-operated and higher TM treated animals. Lower TM had a profound inhibitory effect on plasma inflammatory response and lipid profile in atherosclerotic ApoE(-/-) mice. In addition, we found that the ApoE(-/-) mice presented higher autophagy activity in response to lower TM administration while apoptosis was reduced. An in vitro study in murine macrophages revealed that lower TM could markedly reduce lipid uptake and accumulation and cell apoptosis while significantly upregulated the expression of Atg7. However, higher TM had adverse effects. Finally, mild induction of ERS by lower TM inhibits AKT-TSC-mTOR cascades to increase cellular autophagy. However, high TM failed to enhance autophagy and equilibrate elevated CHOP-mediated cell death in spite of the inhibition of AKT-TSC-mTOR signaling. In conclusion, lower TM stabilized plaques by activating autophagy through AKT-TSC-mTOR signaling.
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Zhaole
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Congye
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China. Electronic address: zhangym197951@126.com.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi 710032, PR China. Electronic address: liyanfmmu@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014415:Tunicamycin / Q000008:administration & dosage*
chemical_list: D014415:Tunicamycin
keywords: Atherosclerosis; Autophagy; Endoplasmic reticulum stress; Plaque stability; Tunicamycin