PMID- 30654511 OWN - NLM STAT- MEDLINE DCOM- 20190429 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 2 DP - 2019 Jan 16 TI - Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis. LID - 10.3390/ijms20020360 [doi] LID - 360 AB - In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson's staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1beta maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-beta1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFbeta1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis. FAU - Pan, Xi-Chun AU - Pan XC AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. xichunpan@tmmu.edu.cn. FAU - Liu, Ya AU - Liu Y AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. liuya1979@hotmail.com. FAU - Cen, Yan-Yan AU - Cen YY AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. cenyanyan@163.com. FAU - Xiong, Ya-Lan AU - Xiong YL AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. xyl11594@sina.com. FAU - Li, Jing-Mei AU - Li JM AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. Jingmei382@163.com. FAU - Ding, Yuan-Yuan AU - Ding YY AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. dingyy@yaopharma.com. FAU - Tong, Yang-Fei AU - Tong YF AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. tongyangfei@gmail.com. FAU - Liu, Tao AU - Liu T AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. cedarliu@foxmail.com. FAU - Chen, Xiao-Hong AU - Chen XH AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. pharma821@163.com. FAU - Zhang, Hai-Gang AU - Zhang HG AD - Department of Pharmacology, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing 400038, China. hgzhang@tmmu.edu.cn. LA - eng GR - 81872911/National Natural Science Foundation of China/ GR - 81573440/National Natural Science Foundation of China/ GR - cstc2016jcyjA0583/Natural Science Foundation of Chongqing/ PT - Journal Article DEP - 20190116 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Diterpenes) RN - 0 (Epoxy Compounds) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Phenanthrenes) RN - 0 (Smad Proteins) RN - 0 (Transforming Growth Factor beta1) RN - 11128-99-7 (Angiotensin II) RN - 19ALD1S53J (triptolide) RN - 9007-34-5 (Collagen) RN - L628TT009W (Isoproterenol) SB - IM MH - Angiotensin II MH - Animals MH - Collagen/metabolism MH - Diterpenes/*pharmacology MH - Down-Regulation/drug effects MH - Enzyme Activation/drug effects MH - Epoxy Compounds/pharmacology MH - Fibroblasts/drug effects/metabolism MH - Fibrosis MH - Heart Ventricles/pathology MH - Inflammasomes/*metabolism MH - Isoproterenol MH - MAP Kinase Signaling System/drug effects MH - Male MH - Mice, Inbred C57BL MH - Myocardium/*metabolism/*pathology MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Phenanthrenes/*pharmacology MH - Smad Proteins/metabolism MH - Transforming Growth Factor beta1/metabolism PMC - PMC6359320 OTO - NOTNLM OT - NOD-like receptor protein 3 OT - apoptosis-associated speck-like protein containing a CARD OT - cardiac fibrosis OT - inflammasome OT - triptolide COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/01/19 06:00 MHDA- 2019/04/30 06:00 PMCR- 2019/01/01 CRDT- 2019/01/19 06:00 PHST- 2018/11/28 00:00 [received] PHST- 2018/12/29 00:00 [revised] PHST- 2019/01/11 00:00 [accepted] PHST- 2019/01/19 06:00 [entrez] PHST- 2019/01/19 06:00 [pubmed] PHST- 2019/04/30 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - ijms20020360 [pii] AID - ijms-20-00360 [pii] AID - 10.3390/ijms20020360 [doi] PST - epublish SO - Int J Mol Sci. 2019 Jan 16;20(2):360. doi: 10.3390/ijms20020360.