Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation.
Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation.
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肉桂醛和别嘌呤醇通过减弱 CD36 介导的 TLR4/6-IRAK4/1 信号传导抑制 NLRP3 炎性体激活，减少果糖诱导的心脏炎症和纤维化
DOI：
10.1038/srep27460
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发表时间：
2016-06-08
影响因子：
4.6
通讯作者：
Kong LD
中科院分区：
文献类型：
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作者：
Kang LL;Zhang DM;Ma CH;Zhang JH;Jia KK;Liu JH;Wang R;Kong LD
果糖消耗诱导代谢综合征增加心血管疾病的风险。肉桂醛和别嘌呤醇具有抗氧化和抗炎活性，可减轻代谢综合征的心脏损伤。但果糖致心肌损伤的机制以及肉桂醛和别嘌呤醇的心肌保护作用尚不完全清楚。在这项研究中，果糖喂养的大鼠表现出代谢综合征，血清ox-LDL升高，心脏氧化应激，炎症和纤维化。在动物模型和H9 c2细胞模型中，清道夫受体CD 36、Toll样受体4（TLR 4）、TLR 6、IL-1 R相关激酶4/1（IRAK 4/1）、核苷酸结合域（NOD）样受体蛋白3（NLRP 3）炎性体、白细胞介素-1 β、转化生长因子-β（TGF-β）、果蝇母体抗DPP同源物（Smad）2/3磷酸化和Smad 4增加。在用ROS清除剂和CD 36特异性抑制剂或IRAK 1/4抑制剂预处理并用CD 36、NLRP 3或IRAK 4/1 siRNA转染的ox-LDL或果糖暴露的H9 c2细胞中进一步评估这些病理过程，表明通过CD 36介导的TLR 4/6-IRAK 4/1信号传导的NLPR 3炎性小体活化可能促进心脏炎症和纤维化。肉桂醛和别嘌呤醇通过在果糖诱导下抑制CD 36介导的TLR 4/6-IRAK 4/1信号传导来降低心脏氧化应激以抑制NLPR 3炎性体活化和TGF-β/Smads信号传导。这些结果表明，通过肉桂醛和别嘌呤醇阻断CD 36介导的TLR 4/6-IRAK 4/1信号传导以抑制NLRP 3炎性体活化可以保护免受果糖诱导的心脏炎症和纤维化。
Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis. Scavenger receptor CD36, Toll-like receptor 4 (TLR4), TLR6, IL-1R-associated kinase 4/1 (IRAK4/1), nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, interleukin-1β, transforming growth factor-β (TGF-β), drosophila mothers against DPP homolog (Smad) 2/3 phosphorylation and Smad4 were increased in animal and H9c2 cell models. These pathological processes were further evaluated in ox-LDL or fructose-exposed H9c2 cells pretreated with ROS scavenger and CD36 specific inhibitor, or IRAK1/4 inhibitor and transfected withCD36,NLRP3, orIRAK4/1siRNA, demonstrating that NLPR3 inflammasome activation through CD36-mediated TLR4/6-IRAK4/1 signaling may promote cardiac inflammation and fibrosis. Cinnamaldehyde and allopurinol reduced cardiac oxidative stress to suppress NLPR3 inflammasome activation and TGF-β/Smads signaling by inhibiting CD36-mediated TLR4/6-IRAK4/1 signaling under fructose induction. These results suggest that the blockage of CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation by cinnamaldehyde and allopurinol may protect against fructose-induced cardiac inflammation and fibrosis.