HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis

Bian, Shuai; Yang, Le; Zhao, Dongfang; Lv, Lizhi; Wang, Tiezheng; Hai, Yong

doi:10.1007/s00011-023-01694-3

Cited by 7 publications

(2 citation statements)

References 48 publications

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“…However, if this signaling pathway is significant or prolonged, it can initiate the progression of other cellular damage mechanisms and subsequently lead to tissue damage. HMGB1 typically interacts with receptors such as RAGE/TLR4/TLR2, which are located on myocardial cell membranes [ 61 – 63 ]. We used RT‒qPCR to assess the levels of these receptors in mouse myocardial tissue before and after DOX stimulation and NETs inhibition.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo–Yap pathway to exacerbate doxorubicin-induced cardiotoxicity

Zhao,

Li,

et al. 2024

Cell. Mol. Life Sci.

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Doxorubicin-induced cardiotoxicity (DIC), which is a cardiovascular complication, has become the foremost determinant of decreased quality of life and mortality among survivors of malignant tumors, in addition to recurrence and metastasis. The limited ability to accurately predict the occurrence and severity of doxorubicin-induced injury has greatly hindered the prevention of DIC, but reducing the dose to mitigate side effects may compromise the effective treatment of primary malignancies. This has posed a longstanding clinical challenge for oncologists and cardiologists. Ferroptosis in cardiomyocytes has been shown to be a pivotal mechanism underlying cardiac dysfunction in DIC. Ferroptosis is influenced by multiple factors. The innate immune response, as exemplified by neutrophil extracellular traps (NETs), may play a significant role in the regulation of ferroptosis. Therefore, the objective of this study was to investigate the involvement of NETs in doxorubicin-induced cardiomyocyte ferroptosis and elucidate their regulatory role. This study confirmed the presence of NETs in DIC in vivo. Furthermore, we demonstrated that depleting neutrophils effectively reduced the occurrence of doxorubicin-induced ferroptosis and myocardial injury in DIC. Additionally, our findings showed the pivotal role of high mobility group box 1 (HMGB1) as a critical molecule implicated in DIC and emphasized its involvement in the modulation of ferroptosis subsequent to NETs inhibition. Mechanistically, we obtained preliminary evidence suggesting that doxorubicin-induced NETs could modulate yes-associated protein (YAP) activity by releasing HMGB1, which subsequently bound to toll like receptor 4 (TLR4) on the cardiomyocyte membrane, thereby influencing cardiomyocyte ferroptosis in vitro. Our findings suggest that doxorubicin-induced NETs modulate cardiomyocyte ferroptosis via the HMGB1/TLR4/YAP axis, thereby contributing to myocardial injury. This study offers a novel approach for preventing and alleviating DIC by targeting alterations in the immune microenvironment.

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Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo–Yap pathway to exacerbate doxorubicin-induced cardiotoxicity

Zhao,

Li,

et al. 2024

Cell. Mol. Life Sci.

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“…The HMGB family, including HMGB1–4, acts as pro-inflammatory mediators in a variety of diseases [ 12 ]. Of the four HMGB members, HMGB1 affects AAA progression by regulating the necroptosis in Ang-II-induced AAA model in APOE −/− mice [ 13 ]. The amino acid sequences of HMGB1 and HMGB2 are highly similar [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

HMGB2 Deficiency Mitigates Abdominal Aortic Aneurysm by Suppressing Ang-II-Caused Ferroptosis and Inflammation via NF-κβ Pathway

Wu,

Chen,

et al. 2023

Mediators of Inflammation

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Background. Ferroptosis is a new form of cell death, which is closely related to the occurrence of many diseases. Our work focused on the mechanism by which HMGB2 regulate ferroptosis and inflammation in abdominal aortic aneurysm (AAA). Methods. Reverse transcription–quantitative polymerase chain reaction and western blot were utilized to assess HMGB2 levels. CCK-8 and flow cytometry assays were utilized to measure cell viability and apoptosis. We detected reactive oxygen species generation, Fe2+ level, and ferroptosis-related protein levels in Ang-II-treated VSMCs, which were typical characteristics of ferroptosis. Finally, the mice model of AAA was established to verify the function of HMGB2 in vivo. Results. Increased HMGB2 level was observed in Ang-II-treated VSMCs and Ang-II-induced mice model. HMGB2 depletion accelerated viability and impeded apoptosis in Ang-II-irritatived VSMCs. Moreover, HMGB2 deficiency neutralized the increase of ROS in VSMCs caused by Ang-II. HMGB2 silencing considerably weakened Ang-II-caused VSMC ferroptosis, as revealed by the decrease of Fe2+ level and ACSL4 and COX2 levels and the increase in GPX4 and FTH1 levels. Furthermore, the mitigation effects of shHMGB2 on Ang-II-induced VSMC damage could be counteracted by erastin, a ferroptosis agonist. Mechanically, HMGB2 depletion inactivated the NF-κβ signaling in Ang-II-treated VSMCs. Conclusions. Our work demonstrated that inhibition of HMGB2-regulated ferroptosis and inflammation to protect against AAA via NF-κβ signaling, suggesting that HMGB2 may be a potent therapeutic agent for AAA.

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Regulated cell death‐amplified sonodynamic anti‐tumor immune nanotherapeutics

Zhou,

Chen,

Xie

et al. 2024

BMEMat

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Nanomedicine‐assisted sonodynamic therapy (SDT) has emerged as one of the most promising cancer therapies due to its unique advantages of high penetration, non‐radiation, and excellent oxidative stress effect, but has always suffered from the self‐protection mechanism and apoptosis resistance characteristics of evolutionarily mutated cancer cells. Regulated cell death (RCD) has received increasing attention in precision cancer treatments because of its significant role in synergistically sensitizing apoptosis and reversing the immunosuppressive microenvironment during SDT nanomedicine‐triggered immunogenic cell death. Herein, paradigmatic research of RCD‐augmented sonodynamic tumor immunotherapeutics are typically introduced, such as autophagy blockade, ferroptosis targeting, pyroptosis induction, necroptosis initiation, cuproptosis actuation, PANoptosis trigger, and the coordinated anti‐tumor mechanisms are discussed in detail. Multiple analysis focusing on the currently unsolved problems and future development prospects of RCD‐based SDT nano‐oncology medicine are also discussed and prospected to further strengthen and expand the scope of its therapeutic applications.

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HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis

Cited by 7 publications

References 48 publications

Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo–Yap pathway to exacerbate doxorubicin-induced cardiotoxicity

Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo–Yap pathway to exacerbate doxorubicin-induced cardiotoxicity

HMGB2 Deficiency Mitigates Abdominal Aortic Aneurysm by Suppressing Ang-II-Caused Ferroptosis and Inflammation via NF-κβ Pathway

Regulated cell death‐amplified sonodynamic anti‐tumor immune nanotherapeutics

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