Mechanistic Insight into the Attenuation of the NLRP3 Inflammasome by Candesartan

• Main Authors: HSIAO,YA-YUN, 蕭雅云
• Other Authors: Peng,YI-JEN
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/5e58js

碩士 === 國防醫學院 === 病理及寄生蟲學研究所 === 106 === Candesartan is one of the angiotensin II receptor antagonists, which is the widely used blood pressure lowering drug. Studies indicate that aberrant activation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is involved in the pathogenesis of many metabolic diseases. Therefore, NLRP3 inflammasome activity and the associated signalling pathways are common targets for next-generation therapeutics. Recent studies have shown that angiotensin receptor antagonists can inhibit the inflammatory reactions triggered by angiotensin type 1 receptor in brain, nerves and blood vessels. However, the effect of Candesartan on the NLRP3 inflammasome remains unexplored. The aim of the present study is to investigate the inhibitory potential of Candesartan towards the NLRP3 inflammasome and possible underlying molecular mechanisms. We demonstrated that Candesartan significantly reduced nigericin-mediated activation of caspase-1 and the secretion of interleukin 1β (IL-1β) and interleukin-18 (IL-18) in mouse macrophages. Candesartan also reduced nigericin-mediated secretion of NLRP3 and apoptosis-associated speck like protein containing a caspase recruitment domain (ASC). In the priming signal of NLRP3 inflammasome, Candesartan significantly inhibited the expression of NLRP3 and proIL-1β by reducing nuclear factor-kappaB (NF-κB) activation. In the activation signal, Candesartan inhibited potassium efflux-mediated IL-1β secretion, reduced mitochondrial ROS production and damage. Additionally, Candesartan reduced double-stranded RNA-dependent kinase (PKR) phosphorylation and inhibited the NLRP3 inflammasome assembly by suppressing the binding between NLRP3 and PKR, NIMA-related kinase 7 (NEK7) and ASC. Taken together, our results indicated that Candesartan inhibited the NLRP3 inflammasome and can be repositioned for ameliorating NLRP3-associated complications.