BRD4 inhibition by JQ1 protects against LPS-induced cardiac dysfunction by inhibiting activation of NLRP3 inflammasomes

Li, Wenjun; Shen, XiuFeng; Feng, Shenglan; Liu, Yue; Zhao, Huiying; Zhou, Guohua; Sang, Ming; Sun, Xiaodong; Jiao, Rong; Liu, Fuyuan

doi:10.1007/s11033-022-07377-2

Cited by 6 publications

(2 citation statements)

References 40 publications

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“…RPTOR knockdown also suppressed cell pyroptosis by decreasing the expression of GSDMD and CASP1. GSDMD, which creates holes in the plasma membrane to enable IL-1/IL-18 release and triggers pyroptosis, is the mediator of this process (39,40). It is also known that pyroptosis is featured by activating inflammasomes and CASP1 and the formation of transmembrane pores by GSDMD (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Wu,

Yu,

Wang

et al. 2023

Shock

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Objective Autophagy elevation in endotoxemia plays a protective role by negatively regulating the pyroptosis of vascular endothelial cells, but the molecular mechanisms are still poorly understood. The present study aimed to identify the mechanism underlying autophagy and pyroptosis in endotoxemia. Methods Bioinformatics analysis and whole-gene transcriptome sequencing prediction were used to identify the endotoxemia-related lncRNA-miRNA-mRNA axis of interest. Human umbilical vein endothelial cells (HUVECs) were activated by lipopolysaccharide (LPS) to mimic the inflammatory environment encountered in endotoxemia. Autophagy and pyroptosis of LPS-treated HUVECs were assessed in response to the knockdown of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) /miR-433-3p (miRNA-433-3p) / RPTOR (regulatory associated protein of mTOR). The binding affinity of MALAT1, miR-433-3p, and RPTOR was detected by RNA pull-down and luciferase activity assays. The endothelial cell-specific RPTOR knockout mice were developed and rendered septic using LPS induction to verify the role of RPTOR in autophagy, pyroptosis, and inflammatory response in vivo. Results The in vitro experiments indicated that LPS could stimulate HUVECs to highly express RPTOR, and its knockdown enhanced cellular autophagy and restricted pyroptosis to curb inflammatory responses. Mechanically, MALAT1 is competitively bound to miR-433-3p to release RPTOR expression, thereby promoting pyroptosis and aggravating endotoxemia. In vivo experiments further confirmed that the knockdown of RPTOR activated autophagy and curtailed pyroptosis in septic mice. Conclusion MALAT1 is highly expressed in endotoxemia. MALAT1 promotes RPTOR expression by competitively absorbing miR-433-3p, inhibits LPS-activated HUVEC cell autophagy, promotes cell death, enhances LPS-induced inflammatory activation of vascular endothelial cells, and ultimately promotes the progression of endotoxemia.

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Section: Discussionmentioning

confidence: 99%

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Wu,

Yu,

Wang

et al. 2023

Shock

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“…Studies have found that doxorubicin upregulates NADPH oxidase 1 and NADPH oxidase 4 expression, thereby activating dynamin-related protein-1and promoting mitochondrial fission, leading to excessive accumulation of ROS in mitochondria and activation of the NLRP3 inflammasome and caspase-1dependent apoptosis ( 126 , 127 ) Certain studies have found that GSDMD knockout significantly decreases NLRP3 and caspase-1 expression, increases survival and improves cardiac dysfunction in mice ( 128 , 129 ). Moreover, LPS directly affects nuclear localization of sting and interferon regulatory factor-3-activated sting then activates NLRP3, leading to cardiac dysfunction as well as pyroptosis ( 130 ). Collectively, pyroptosis is induced in most forms of cardiomyopathy and blocking pyroptosis by direct or indirect approaches that target the pyroptotic machinery or upstream regulators may exert a protective effect.…”

Section: Association Between Cell Death and Scmentioning

confidence: 99%

Sepsis‑induced cardiac dysfunction and pathogenetic mechanisms (Review)

Song,

Fang,

Zhou

et al. 2023

Mol Med Rep

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Sepsis is a manifestation of the immune and inflammatory response to infection, which may lead to multi-organ failure. Health care advances have improved outcomes in critical illness, but it still remains the leading cause of death. Septic cardiomyopathy is heart dysfunction brought on by sepsis. Septic cardiomyopathy is a common consequence of sepsis and has a mortality rate of up to 70%. There is a lack of understanding of septic cardiomyopathy pathogenesis; knowledge of its pathogenesis and the identification of potential therapeutic targets may reduce the mortality rate of patients with sepsis and lead to clinical improvements. The present review aimed to summarize advances in the pathogenesis of cardiac dysfunction in sepsis, with a focus on mitochondrial dysfunction, metabolic changes and cell death modalities and pathways. The present review summarized diagnostic criteria and outlook for sepsis treatment, with the goal of identifying appropriate treatment methods for this disease.

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Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach

Chowdhury,

Karmakar

2023

Mol Biol Rep

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BRD4 inhibition by JQ1 protects against LPS-induced cardiac dysfunction by inhibiting activation of NLRP3 inflammasomes

Cited by 6 publications

References 40 publications

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

Sepsis‑induced cardiac dysfunction and pathogenetic mechanisms (Review)

Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach

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