Honokiol antagonizes doxorubicin-induced cardiomyocyte senescence by inhibiting TXNIP-mediated NLRP3 inflammasome activation
Honokiol antagonizes doxorubicin-induced cardiomyocyte senescence by inhibiting TXNIP-mediated NLRP3 inflammasome activation
复制标题
和厚朴酚通过抑制 TXNIP 介导的 NLRP3 炎性体激活来拮抗阿霉素诱导的心肌细胞衰老。
DOI：
10.3892/ijmm.2019.4393
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发表时间：
2020-01-01
影响因子：
5.4
通讯作者：
Qi, Ben-Ling
中科院分区：
文献类型：
--
作者：
Huang, Pian-Pian;Fu, Jun;Qi, Ben-Ling
心肌细胞的衰老被认为是阿霉素（Dox）相关性心肌病发生的关键因素。据报道，NOD样受体家族的含pyrin结构域3（NLRP 3）炎性体参与细胞衰老过程。此外，硫氧还蛋白相互作用蛋白（TXNIP）是NLRP 3炎性小体激活所必需的，被认为是衰老发病机制调节的关键组分。研究表明，和诺啡肽（Hnk）预处理可减轻Dox引起的心脏毒性。然而，Hnk对Dox诱导的心肌细胞衰老的影响及其机制尚不清楚。本研究表明，Hnk能够防止Dox诱导的H9 c2心肌细胞衰老，这通过减少衰老相关的β-半乳糖苷酶（SA-β-gal）染色以及减少p16（INK 4A）和p21的表达来表示。Hnk还抑制Dox刺激的H9 c2心肌细胞中TXNIP表达和NLRP 3炎性小体激活。当通过腺病毒介导的基因过表达加强TXNIP表达时，NLRP 3炎性体被激活，这导致Hnk对Dox处理的H9 c2心肌细胞的抗炎和抗衰老作用受到抑制。此外，腺病毒介导的TXNIP沉默抑制NLRP 3炎性小体。结论：TXNIP基因敲低可增强Hnk对Dox刺激下H9 c2心肌细胞的抗炎和抗衰老作用。总之，发现Hnk在保护心肌细胞免受Dox刺激的衰老方面是有效的。这种保护作用是通过抑制TXNIP表达和随后抑制NLRP 3炎性体介导的。这些结果表明Hnk可能通过抑制心肌细胞衰老而具有作为心脏保护药物的价值。
Senescence of cardiomyocytes is considered a key factor for the occurrence of doxorubicin (Dox)-associated cardiomyopathy. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is reported to be involved in the process of cellular senescence. Furthermore, thioredoxin-interactive protein (TXNIP) is required for NLRP3 inflammasome activation and is considered to be a key component in the regulation of the pathogenesis of senescence. Studies have demonstrated that pretreatment with honokiol (Hnk) can alleviate Dox-induced cardiotoxicity. However, the impact of Hnk on cardiomyocyte senescence elicited by Dox and the underlying mechanisms remain unclear. The present study demonstrated that Hnk was able to prevent Dox-induced senescence of H9c2 cardiomyocytes, indicated by decreased senescence-associated beta -galactosidase (SA-beta -gal) staining, as well as decreased expression of p16(INK4A) and p21. Hnk also inhibited TXNIP expression and NLRP3 inflammasome activation in Dox-stimulated H9c2 cardiomyocytes. When TXNIP expression was enforced by adenovirus-mediated gene overexpression, the NLRP3 inflammasome was activated, which led to inhibition of the anti-inflammation and anti-senescence effects of Hnk on H9c2 cardiomyocytes under Dox treatment. Furthermore, adenovirus-mediated TXNIP-silencing inhibited the NLRP3 inflammasome. Consistently, TXNIP knockdown enhanced the anti-inflammation and anti-senescence effects of Hnk on H9c2 cardiomyocytes under Dox stimulation. In summary, Hnk was found to be effective in protecting cardio-myocytes against Dox-stimulated senescence. This protective effect was mediated via the inhibition of TXNIP expression and the subsequent suppression of the NLRP3 inflammasome. These results demonstrated that Hnk may be of value as a cardioprotective drug by inhibiting cardiomyocyte senescence.