title: The impact of intermittent and repetitive cold stress exposure on endoplasmic reticulum stress and instability of atherosclerotic plaques.
abstract: BACKGROUND
  The incidence of acute coronary syndrome caused by the rupture of atherosclerotic plaque and subsequent arterial thrombosis increases as the weather gets colder. However, the association between cold stress and atherosclerotic plaque rupture is currently unknown.
  
  
  METHODS
  An atherosclerotic plaque model was established in rabbits by balloon injury and a high-fat diet with or without cold stress (4 °C, 1 hour per day, 20 weeks) at the onset of modeling. Additionally, oxidized low-density lipoprotein (ox-LDL) was applied to induce the formation of macrophage foam cells in vitro.
  
  
  RESULTS
  Serum lipid profiles and inflammatory cytokines (ox-LDL, high-sensitivity C-reactive protein, and interleukin-8) were significantly higher in cold stress-exposed rabbits than in controls (P<0.05). Animals with atherosclerotic lesions that were exposed to cold stress had increased macrophages, foam cells, intima-media thickness, and neovascularization in the plaque, along with significantly thinned plaque fibrous caps. Moreover, we found that cold stress induced more apoptotic cells in the atherosclerotic plaques and up-regulated endoplasmic reticulum stress (ERS)-associated proteins CHOP, GRP78, and p-JNK (P<0.05). In addition, tunicamycin treatment promoted ox-LDL-induced apoptosis, expression of CHOP and GPR78, and the p-JNK level in macrophage foam cells, while JNK inhibitor sp600125 reduced cell apoptosis and the p-JNK level. The three main ERS sensors sensors phosphorylated extracellular signal-regulated kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme1 (IRE1) declined significantly after ox-LDL treatment.
  
  
  CONCLUSIONS
  Cold stress may enhance the instability of atherosclerotic plaques through activating ERS and enhancing cell apoptosis. Up-regulated CHOP levels mediated by PERK and ATF6 and the activated IRE1-XBP1-JNK pathway contributed to the apoptosis of foam cells.
authors: Department of Cardiology, Xijing Hospital, The Fourth Military Medial University, Xi'an, Shaanxi, P.R. China.
authors: Ming-Xiang
authors: MX
authors: Dai
authors: Xiao-Hui
authors: XH
authors: Zheng
authors: Jin
authors: J
authors: Yu
authors: Tao
authors: T
authors: Yin
authors: Mei-Juan
authors: MJ
authors: Ma
authors: Le
authors: L
authors: Zhang
authors: Min
authors: M
authors: Liu
authors: Ying
authors: Y
authors: Ma
authors: Li-Wen
authors: LW
authors: Liu
authors: Xue
authors: X
authors: Gao
authors: Yan
authors: Y
authors: Li
authors: Li-Qiang
authors: LQ
authors: Song
authors: Hai-Chang
authors: HC
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D003080:Cold Temperature; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000503:physiopathology*; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological
chemical_list: D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse