Amelioration of glucolipotoxicity-induced endoplasmic reticulum stress by a "chemical chaperone" in human THP-1 monocytes.
Amelioration of glucolipotoxicity-induced endoplasmic reticulum stress by a "chemical chaperone" in human THP-1 monocytes.
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DOI：
10.1155/2012/356487
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发表时间：
2012
影响因子：
--
通讯作者：
Balasubramanyam M
中科院分区：
文献类型：
--
作者：
Lenin R;Maria MS;Agrawal M;Balasubramanyam J;Mohan V;Balasubramanyam M
慢性内质网应激正逐渐成为导致许多全身和动脉壁因素失衡并促进动脉粥样硬化的触发因素。晚期动脉粥样硬化病变内的巨噬细胞凋亡也被认为会增加动脉粥样硬化血栓性疾病的风险。我们假设糖脂毒性可能通过内质网应激介导单核细胞活化和凋亡。因此，本研究的目的是(a)研究糖脂毒性是否会对THP-1人单核细胞施加内质网应激和凋亡，(b)研究化学伴侣4-苯基丁酸（PBA）是否能抵抗糖脂毒性诱导的内质网应激和凋亡。糖脂毒性或tunicamycin处理的细胞均表现出ROS生成增加，内质网应激标志物的基因和蛋白（PERK、GRP-78、IRE1α和CHOP）表达增加。此外，DNA损伤显示TRPC-6通道表达增加，凋亡增加，caspase-3活性增加。虽然糖脂毒性/tunicamycin增加氧化应激、内质网应激、TRPC-6 mRNA表达，并使THP-1单核细胞凋亡，但PBA能够抵抗这些分子扰动。由于内质网应激是糖尿病和动脉粥样硬化中单核细胞功能障碍的潜在原因之一，我们的研究强调，化学伴侣如PBA可以缓解内质网应激，并有可能成为新的治疗方法。
Chronic ER stress is emerging as a trigger that imbalances a number of systemic and arterial-wall factors and promote atherosclerosis. Macrophage apoptosis within advanced atherosclerotic lesions is also known to increase the risk of atherothrombotic disease. We hypothesize that glucolipotoxicity might mediate monocyte activation and apoptosis through ER stress. Therefore, the aims of this study are (a) to investigate whether glucolipotoxicity could impose ER stress and apoptosis in THP-1 human monocytes and (b) to investigate whether 4-Phenyl butyric acid (PBA), a chemical chaperone could resist the glucolipotoxicity-induced ER stress and apoptosis. Cells subjected to either glucolipotoxicity or tunicamycin exhibited increased ROS generation, gene and protein (PERK, GRP-78, IRE1α, and CHOP) expression of ER stress markers. In addition, these cells showed increased TRPC-6 channel expression and apoptosis as revealed by DNA damage and increased caspase-3 activity. While glucolipotoxicity/tunicamycin increased oxidative stress, ER stress, mRNA expression of TRPC-6, and programmed the THP-1 monocytes towards apoptosis, all these molecular perturbations were resisted by PBA. Since ER stress is one of the underlying causes of monocyte dysfunction in diabetes and atherosclerosis, our study emphasize that chemical chaperones such as PBA could alleviate ER stress and have potential to become novel therapeutics.
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影响因子：
82.9
作者：
Erbay, Ebru;Babaev, Vladimir R.;Mayers, Jared R.;Makowski, Liza;Charles, Khanichi N.;Snitow, Melinda E.;Fazio, Sergio;Wiest, Michelle M.;Watkins, Steven M.;Linton, MacRae F.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
4.3
作者：
Balasubramanyam, M.;Aravind, S.;Mohan, V.
通讯作者：
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影响因子：
7.7
作者：
HIRAMATSU, K;ARIMORI, S
通讯作者：
ARIMORI, S
影响因子：
7.7
作者：
Kaniuk, Natalia A.;Kiraly, Michael;Brumell, John H.
通讯作者：
Brumell, John H.
影响因子：
3.9
作者：
Choi, Sung-E;Lee, Youn-Jung;Kang, Yup
通讯作者：
Kang, Yup