The Impact of Intermittent and Repetitive Cold Stress Exposure on Endoplasmic Reticulum Stress and Instability of Atherosclerotic Plaques

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.