MLKL Aggravates Ox-LDL-Induced Cell Pyroptosis via Activation of NLRP3 Inflammasome in Human Umbilical Vein Endothelial
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ORIGINAL ARTICLE
MLKL Aggravates Ox-LDL-Induced Cell Pyroptosis via Activation of NLRP3 Inflammasome in Human Umbilical Vein Endothelial Cells Qian Wu,1 Xin He,1,2 Li-Mei Wu,1,3 Ru-Yi Zhang,1 Li-Min Li,1,2 Chang-Meng Wu,1 Yuan-Bin Lu,1 Bing Hu,1 Chao Shi,1 Zhi-Feng Lu,1 Biao Yang,1 Lei Zheng,1 Yan-Wei Hu ,1,4,5 and Qian Wang1,2,5
Atherosclerosis is a progressive chronic inflammation in the arterial walls. It is believed that the deposition of low-density lipoprotein (LDL) and its damage to endothelial cells play a vital role in atherosclerosis. Oxidized LDL (Ox-LDL) was confirmed to induce endothelial cell pyroptosis which plays an important role in intima inflammation and the development of atherosclerosis, but the underlying molecular mechanism needs to be explored. Here, we showed that ox-LDL upregulated the expression of mixed lineage kinase domain-like (MLKL) protein at both the mRNA and protein levels in endothelial cells, associated with the augment of pro-caspase-1 cleavage, interleukin-1β (IL-1β) maturation, pro-IL-1β production, and lactate dehydrogenase (LDH) release. Overexpression of MLKL substantially aggravated ox-LDL-induced increasing levels of caspase-1, IL-1β, pro-IL-1β, and LDH. MLKL-induced caspase-1 activation and IL-1β maturation were abolished by NLR family, pyrin domain-containing 3 (NLRP3) specific inhibitor MCC950, or extracellular high potassium concentration. Our findings indicated that MLKL is essential for regulation of ox-LDL-induced pyroptosis and inflammation through the activation of NLRP3 inflammasome, and suggested that MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases. Abstract—
KEY WORDS: Ox-LDL; MLKL; pyroptosis; NLRP3; caspase-1; IL-1β.
many other cardiovascular diseases [1]. The pathogenesis of atherosclerosis is complex and still not fully understood. It is now well accepted that atherosclerosis is a chronic inflammatory disease within the vascular walls. It always
INTRODUCTION Coronary atherosclerosis is the basis of most coronary artery disease (CAD) and leads to the development of Qian Wu and Xin He contributed equally to this work. 1
Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China 2 Laboratory Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China 3 Department of Clinical Laboratory, Guangzhou Twelfth People’s Hospital, Guangzhou, 510620, China
4
Department of Clinical Laboratory, Guangzhou Women & Children Medical Center, Guangzhou Medical University, Guangzhou, China 5 To whom correspondence should be addressed to Yan-Wei Hu at Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. E-mail: [email protected]; and ; [email protected]
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Wu, He, Wu, Zhang, Li, Wu, Lu, Hu, Shi, Lu, Yang, Zheng, Hu, and Wang begins with the damage to the endothelial. After endothelial injury, low-density lipopro
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