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National Chung Hsing University Institutional Repository - NCHUIR > 生命科學院 > 生物醫學研究所 > 依資料類型分類 > 碩博士論文 >  高血糖誘導巨噬細胞自由基媒介的鈣蛋白酶Calpain活化及葡萄糖調節蛋白GRP78/Bip降解

Please use this identifier to cite or link to this item: http://nchuir.lib.nchu.edu.tw/handle/309270000/152681

標題: 高血糖誘導巨噬細胞自由基媒介的鈣蛋白酶Calpain活化及葡萄糖調節蛋白GRP78/Bip降解
Reactive oxygen species mediate high glucose- induced calpain activation and GRP78/BiP degradation in the macrophage
作者: 蔡怡青
Tsai, Yi-Ching
Contributors: 許惠恒
Wayne-Huey-Herng Sheu
生物醫學研究所
關鍵字: 高糖;內質網壓力;葡萄糖調節蛋白78
high glucose;ER stress;GRP78
日期: 2012
Issue Date: 2013-11-18 11:05:06 (UTC+8)
Publisher: 生物醫學研究所
摘要: 高糖誘導過氧化物生成,使巨噬細胞產生內質網壓力,在形成動脈硬化的過程中扮演重要角色。在高糖的環境下巨噬細胞葡萄糖調節蛋白(GRP78/BiP)減少,可能促使動脈硬化的形成。然而其中的機制並不清楚。在此,我們證明RAW 264.7巨噬細胞株及THP-1人類活化的單核細胞在高糖的環境下會增加內質網壓力的指標,並且降低內質網內伴隨蛋白Grp78/Bip的表現。高糖特異地增加過氧化物及鈣蛋白酶(calpain)的活性。抗氧化物顯著的降低上述的效應。Calpain蛋白的表現在免疫組織染色中,不管在高糖或高脂的環境下,STZ誘導的第一型糖尿病、高脂誘導的肥胖鼠其calpain的表現量皆增加。Calpain抑制劑可以避免GRP78/BiP的降解。在生物體內實驗,高脂飲食誘導的肥胖鼠給予PPAR-gamma促效劑後,可有效回復減少的Grp78/Bip,並且改善增加calpain的現象。我們提供一項關於PPAR-gamma促效劑治療糖尿病患的路徑,也就是PPAR-gamma促效劑可能透過誘導HO-1的表現來抑制calpain的活性及蛋白表現進而達到療效。綜合這些證據,巨噬細胞在高糖的誘導下會引起內質網壓力及calpain的活化造成Grp78的降解。
It is well acknowledged that high glucose (HG) increases reactive oxygen species (ROS) production and prolongs activation of the endoplasmic reticulum (ER stress) which involve progression of atherosclerosis in macrophage. The content of glucose regulated protein (GRP78/BiP) is reduced in the macrophage under hyperglycemic conditions and may contribute to the pathogenesis of atherosclerosis. However, the molecular mechanisms are poorly understood. Here, we demonstrated that hyperglycemia markedly increase ER stress marker and decreased macrophage protein levels of glucose regulated protein GRP78/BiP, a chaperone known to mediate ER stress in Raw 264.7 cells and activated human monocyte THP1 cells. High glucose specifically activated ROS production and calpain activity. Antioxidant reagents markedly abolished above-mentioned effect. Calpain protein expression in the artery from STZ-induced diabetic mice and high fat diet-induced obesity mice model were immunohistochemically examined. Exposure calpain inhibitor prevents GRP78/BiP degradation. Administration of a PPAR-gamma agonist, pioglitazone, reversed the GRP78/BiP degradation in a high-fat diet and ameliorated the expression of calpain in vivo. We provide a new information that PPAR-gamma agonist benefit diabetic patients may through induced heme oxygenase-1 (HO-1) to inhibits calpain protein expression and activity. Taken together, these data suggest that, in the macrophage, high glucose induces GRP78 degradation and evokes an ER stress responses that could contribute, in part, to high glucose induced calpain expression.
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