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GW23-e1731
THE ENDOPLASMIC RETICULUM STRESS-JNK PATHWAY-MEDICATED APOPTOSIS IN MACROPHAGES CONTRIBUTES TO THE INSTABILITY OF ATHEROSCLEROTIC PLAQUES INDUCED BY COLD STRESS
  1. Zheng Xiaohui,
  2. Li Yan
  1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China

    Abstract

    Objectives To elucidate whether and how the endoplasmic reticulum(ER) stress-JNK pathway in macrophages is involved in the instability of atherosclerotic plaques induced by cold stress.

    Methods Forty male New Zealand white rabbits fed on high-fat diet for 2 weeks following by balloon injury of abdominal aorta were randomly divided into two groups: Cold-stress group and control group. Cold-stress group were exposed to cold (4°C) for 1 h per day for 20 weeks. The animals were sacrificed and then the pathological changes of atherosclerotic plaques were evaluated. Ultrasonography, contrast-enhanced ultrasonography and immunohistochemistry were used to evaluate IMT (intima-media thickness), angiogenesis and macrophage infiltration. Instability of plaque was evaluated with protocol designed instability score chart. Serum levels of blood lipid, ox-LDL, hs-CRP and IL-8 were determined by ELISA. GRP78 and CHOP expression were determined by western-blot. In vitro, macrophages were stimulated by different concentration (25 mg/l, 50 mg/l, 100 mg/l) of ox-LDL. And sp600125 was used to inhibit the phosphorylation of JNK. After 24 h, the intracellular lipid accumulation in macrophage was determined by Oil Red O staining. The indicator of endoplasmic reticulum stress GRP78, CHOP and JNK, p-JNK and Caspase-3 expression were determined by the western-blot analysis.

    Results After cold stress treatment, ox-LDL, hs-CRP and IL-8 (all p<0.05 vs control group)were significantly increased; pronounced intimal thickening, plaque formation and angiogenesis in plaques increased significantly (p<0.05 vs control group); plaque lipid cores were greater and plaque fibrous caps were thinner; less collagen fibers while more macrophages were observed (p<0.05 vs control group); higher instability scores were obtained(p<0.05 vs control group); the expression of endoplasmic reticulum stress markers GRP78, CHOP increased significantly (p<0.05vs control group). In vitro, we found that macrophages could be induced to transform into foam cells by ox-LDL in dose dependent way, while JNK inhibitor mitigated this effect (p<0.05 vs 100 mg/l group). ER stress marker protein GRP78 and CHOP increased markedly (p<0.05 vs 100 mg/l group). Inhibition of JNK phosphorlation resulted in decrease in level of apoptosis and caspase 3 (p<0.05 vs 100 mg/l group)

    Conclusions The ER stress-JNK-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques by cold stress.

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