Honokiol antagonizes doxorubicin‑induced cardiomyocyte senescence by inhibiting TXNIP‑mediated NLRP3 inflammasome activation

Abstract

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 β-galactosidase (SA-β-gal) staining, as well as decreased expression of p16INK4A 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.

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

“…Moreover, supporting action on islet biology was concurrently revealed in another study through reversion of impaired endothelial cell angiogenic function, generation of VEGF, and sensitivity to VEGF activities [ 26 , 64 ]. Recently, TXNIP-knockdown has shown improved anti-senescence and anti-inflammation effects on H9c2 cardiomyocytes under doxorubicin-associated cardiomyopathy [ 70 ].…”

Accelerated, severe lupus nephritis benefits from treatment with honokiol by immunoregulation and differentially regulating NF‐κB/NLRP3 inflammasome and sirtuin 1/autophagy axis

“…18 We further demonstrated that HNK inhibits T cell proliferation and dendritic cell differentiation. 19 Consistently, HNK has also been shown to preserve mitochondria and to protect the heart in cardiomyopathy 20,21 and the liver in bacterial infection 22 in mice.…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…Conversely, TXNIP has a pro-inflammatory role leading to cardiac, vascular and endothelial dysfunctions [ 13 , 19 , 21 , 66 , 67 , 68 , 143 , 144 ]. Numerous studies conducted since the 2000s suggest that TXNIP may bind to the NLRP3 inflammasome, which enhances the inflammatory response, as reviewed almost a decade ago [ 65 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ] and summarized in Figure 1 . TXNIP and NLRP3 physically interact to activate the inflammasome [ 83 ].…”

“…The expression of inflammatory markers and adhesion molecules such as ICAM-1, VCAM-1, and MCP-1 are diminished in VSMCs from TXNIP knockout mice [ 110 ]. This inflammation state can trigger cell senescence or cell death characterized as pyroptosis, which is hampered with the decrease of TXNIP [ 66 , 78 , 92 , 93 , 105 ]. The ROS-TXNIP-NLRP3 pathway can actually be enabled for a long time via an IL-1β-mediated positive feedback loop [ 145 ].…”