DL-3-n-Butylphthalide Attenuates Myocardial Hypertrophy by Targeting Gasdermin D and Inhibiting Gasdermin D Mediated Inflammation

Han, Bingjiang; Xu, Jiajun; Shi, Xiaowen; Zheng, Zhanxiong; Shi, Fengjie; Jiang, Fenfen; Han, Jibo

doi:10.3389/fphar.2021.688140

Cited by 15 publications

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“…17 In our previous study, we showed that pharmacological inhibition of GSDMD reversed TAC-induced cardiac hypertrophy. 13,14 Despite these promising findings, the direct effect of GSDMD deficiency on myocardial hypertrophy and GSDMD-related downstream pathogenic mechanisms have not been fully elucidated.…”

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confidence: 99%

“…17 In our previous study, we showed that pharmacological inhibition of GSDMD reversed TACinduced cardiac hypertrophy. 13,14 Despite these promising findings, the direct effect of GSDMD deficiency on myocardial hypertrophy and GSDMD-related downstream pathogenic mechanisms have not been fully elucidated. STING (stimulator of interferon genes), as an integral adaptor protein of innate immunity, can recognize both the classical second messengers produced by pathogenic microorganisms and nonclassical cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAS (cyclic GMP-AMP synthase) and cytosolic DNA.…”

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confidence: 99%

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GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

et al. 2022

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Background: Cardiac hypertrophy is initially an adaptive response of cardiomyocytes to neurohumoral or hemodynamic stimuli. Evidence indicates that Ang II (angiotensin II) or pressure overload causes GSDMD (gasdermin D) activation in cardiomyocytes and myocardial tissues. However, the direct impact of GSDMD on cardiac hypertrophy and its underlying mechanisms are not fully understood. Methods and Results: In this study, we examined the aberrant activation of GSDMD in mouse and human hypertrophic myocardia, and the results showed that GSDMD deficiency reduced Ang II or pressure overload–induced cardiac hypertrophy, dysfunction, and associated cardiomyocyte pyroptosis in mice. Mechanistically, Ang II–mediated GSDMD cleavage caused mitochondrial dysfunction upstream of STING (stimulator of interferon genes) activation in vivo and in vitro. Activation of STING, in turn, potentiated GSDMD-mediated cardiac hypertrophy. Moreover, deficiency of both GSDMD and STING suppressed cardiac hypertrophy in cardiac-specific GSDMD-overexpressing mice. Conclusions: Based on these findings, we propose a mechanism by which GSDMD generates a self-amplifying, positive feed-forward loop with the mitochondria-STING axis. This finding points to the prospects of GSDMD as a key therapeutic target for hypertrophy-associated heart diseases.

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GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

et al. 2022

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“…The signal transduction mechanism underlying MH is complex. Inflammation ( 70 ) and oxidative stress ( 71 ) have both been previously demonstrated to cause alterations leading to MH and heart failure. A previous systematic study of Wnt on a genome-wide level reported an association between MH and the Wnt expression profile ( 72 ).…”

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Puerarin attenuates isoproterenol‑induced myocardial hypertrophy via inhibition of the Wnt/β‑catenin signaling pathway

Wang

et al. 2022

Mol Med Rep

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Myocardial hypertrophy (MH) is an independent risk factor for cardiovascular disease, which in turn lead to arrhythmia or heart failure. Therefore, attention must be paid to formulation of therapeutic strategies for MH. Puerarin is a key bioactive ingredient isolated from Pueraria genera of plants that is beneficial for the treatment of MH. However, its molecular mechanism of action has not been fully determined.In the present study, 40 µM puerarin was demonstrated to be a safe dose for human AC16 cells using Cell Counting Kit-8 assay. The protective effects of puerarin against MH were demonstrated in AC16 cells stimulated with isoproterenol (ISO). These effects were characterized by a significant decrease in surface area of cells (assessed using fluorescence staining) and mRNA and protein expression levels of MH-associated biomarkers, including atrial and brain natriuretic peptide, assessed using reverse transcription-quantitative PCR and western blotting, as well as β-myosin heavy chain mRNA expression levels. Mechanistically, western blotting demonstrated that puerarin inhibited activation of the Wnt signaling pathway. Puerarin also significantly decreased phosphorylation of p65; this was mediated via crosstalk between the Wnt and NF-κB signaling pathways. An inhibitor (Dickkopf-1) and activator (IM-12) of the Wnt signaling pathway were used to demonstrate that puerarin-mediated effects alleviated ISO-induced MH via the Wnt signaling pathway. The results of the present study demonstrated that puerarin pre-treatment may be a potential therapeutic strategy for preventing ISO-induced MH and managing MH in the future.

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“…For instance, Fu et al showed that the NLRP3 inhibitor MCC950 and caspase-1 i n h i b i t o r A c -Y V A D -C M K a m e l i o r a t e d i n c r e a s e d hippocampal neuronal pyroptosis and reduced the levels of pro-inflammatory cytokines and rescued cognitive deficits in mice with sepsis-associated encephalopathy (Fu et al, 2019). Besides, there are several drugs reported to target GSDMD directly and block pyroptosis, including necrosulfonamide (NSA), disulfiram and DL-3-n-butylphthalide (Rathkey et al, 2018;Hu et al, 2020;Han et al, 2021). For instance, Rathkey et al reported that NSA treatment attenuated release of inflammatory cytokine and significantly prolonged survival in a mouse model of sepsis, providing the basis for developing novel therapies for sepsis and other inflammatory diseases (Rathkey et al, 2018).…”

Section: Pyroptosis As a Therapeutic Target In Sepsismentioning

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Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction

Wen

Liu

Tong

et al. 2022

Front. Cell. Infect. Microbiol.

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Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in intensive care units. The development of sepsis-associated organ dysfunction (SAOD) poses a threat to the survival of patients with sepsis. Unfortunately, the pathogenesis of sepsis and SAOD is complicated, multifactorial, and has not been completely clarified. Recently, numerous studies have demonstrated that pyroptosis, which is characterized by inflammasome and caspase activation and cell membrane pore formation, is involved in sepsis. Unlike apoptosis, pyroptosis is a pro-inflammatory form of programmed cell death that participates in the regulation of immunity and inflammation. Related studies have shown that in sepsis, moderate pyroptosis promotes the clearance of pathogens, whereas the excessive activation of pyroptosis leads to host immune response disorders and SAOD. Additionally, transcription factors, non-coding RNAs, epigenetic modifications and post-translational modifications can directly or indirectly regulate pyroptosis-related molecules. Pyroptosis also interacts with autophagy, apoptosis, NETosis, and necroptosis. This review summarizes the roles and regulatory mechanisms of pyroptosis in sepsis and SAOD. As our understanding of the functions of pyroptosis improves, the development of new diagnostic biomarkers and targeted therapies associated with pyroptosis to improve clinical outcomes appears promising in the future.

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DL-3-n-Butylphthalide Attenuates Myocardial Hypertrophy by Targeting Gasdermin D and Inhibiting Gasdermin D Mediated Inflammation

Cited by 15 publications

References 26 publications

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis

Puerarin attenuates isoproterenol‑induced myocardial hypertrophy via inhibition of the Wnt/β‑catenin signaling pathway

Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction

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