期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 86, 期 -, 页码 62-74出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.07.010
关键词
Mitochondrial fission; Endoplasmic reticulum stress; AMPK; NLRP3 inflammasome; Endothelial dysfunction
资金
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization
- Qing Lan Project in Jiangsu Province
- China Scholarship Council (CSC)-National Scholar-ship [201307060036]
Background and purpose: This study aims to investigate whether and how pharmacological activation of AMP-activated protein kinase (AMPK) improves endothelial function by suppressing mitochondrial ROS-associated endoplasmic reticulum stress (ER stress) in the endothelium. Experimental approach Palmitate stimulation induced mitochondrial fission and ER stress-associated endothelial dysfunction. The effects of AMPK activators salicylate and AICA riboside (AICAR) on mitochondrial ROS production, Drp1 phosphorylation, mitochondrial fission, ER stress, thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation, inflammation, cell apoptosis and endothelium-dependent vasodilation were observed. Key results Silencing of TXNIP by RNA interference inhibited NLRP3 inflammasome activation in response to ER stress, indicating that TXNIP was a key link between ER stress and NLRP3 inflammasome activation. AMPK activators salicylate and AICAR prevented ROS-induced mitochondrial fission by enhancing dynamin-related protein I (Drp1) phosphorylation (Set 637) and thereby attenuated IRE-la and PERK phosphorylation, but their actions were blocked by knockdown of AMPK Salicylate and AICAR reduced TXNIP induction and inhibited NLRP3 inflammasome activation by reducing NLRP3 and caspase-1 expression, leading to a reduction in IL-1 beta secretion. As a result, salicylate and AICAR inhibited inflammation and reduced cell apoptosis. Meanwhile, salicylate and AICAR enhanced eNOS phosphorylation and restored the loss of endothelium-dependent vasodilation in the rat aorta. Immunohistochemistry staining showed that AMPK activation inhibited ER stress and NLRP3 inflammasome activation in the vascular endothelium. Conclusion and implications: Pharmacological activation of AMPK regulated mitochondrial morphology and ameliorated endothelial dysfunction by suppression of mitochondrial ROS-associated ER stress and subsequent TXNIP/NLRP3 inflammasome activation. These findings suggested that regulation of Drp1 phosphorylation by AMPK activation contributed to suppression of ER stress and thus presented a potential therapeutic strategy for AMPK activation in the regulation of endothelium homeostasis. (C) 2015 Elsevier Ltd. All rights reserved.
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