Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury

Chen, Xudong; Lin, Shuang; Dai, Shanshan; Han, Jibo; Shan, Peiren; Wang, Weiqi; Huang, Zhouqing; Ye, Bozhi; Huang, Weijian

doi:10.1007/s00011-021-01530-6

Cited by 17 publications

(14 citation statements)

References 48 publications

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“…In addition, by targeting the Akt/GSK3β/NF-κB pathway, aesculin can inhibit NLRP3 inflammasome-mediated pyroptosis and thereby attenuate myocardial I/R injury [ 78 ]. Apart from the aforementioned drugs, ethyl acetate extract of cinnamomi ramulus, cinnamic acid, igramomod, piperazine ferulate, sevoflurane, trimetazidine, tubastatin, geniposide, intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1), and a soluble receptor for late glycation end products have all been found to have protective effects against myocardial I/R injury [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Additionally, sweroside can also protect against myocardial I/R injury partly by regulating the Keap1/Nrf2/NLRP3 axis to inhibit oxidative stress and pyroptosis [ 89 ].…”

Section: Pyroptosis and I/r Injurymentioning

confidence: 99%

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

Zheng

Chi

et al. 2022

Biomolecules

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Ischemia-reperfusion (I/R) injury, uncommon among patients suffering from myocardial infarction, stroke, or acute kidney injury, can result in cell death and organ dysfunction. Previous studies have shown that different types of cell death, including apoptosis, necrosis, and autophagy, can occur during I/R injury. Pyroptosis, which is characterized by cell membrane pore formation, pro-inflammatory cytokine release, and cell burst, and which differentiates itself from apoptosis and necroptosis, has been found to be closely related to I/R injury. Therefore, targeting the signaling pathways and key regulators of pyroptosis may be favorable for the treatment of I/R injury, which is far from adequate at present. This review summarizes the current status of pyroptosis and its connection to I/R in different organs, as well as potential treatment strategies targeting it to combat I/R injury.

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Section: Pyroptosis and I/r Injurymentioning

confidence: 99%

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

Zheng

Chi

et al. 2022

Biomolecules

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“…Pyroptosis directly leads to the death of cardiomyocytes, which reduces the number of effective cardiomyocytes, thereby affecting the systolic and diastolic functions of the myocardium and promoting cardiac remodeling in HF. In adult mouse cardiomyocytes, the absence of GSDMD markedly blocked H/R-induced cardiomyocyte pyroptosis, which is associated with N-terminal fragment cleavage release ( 94 , 95 ). Immunoblot analysis revealed significantly increased levels of GSDMD and GSDMD-N after H/R in adult mouse cardiomyocytes in a time-dependent manner, bring with large numbers of balloon-shaped vesicles and accumulation of propidium iodide (PI), which are typical characteristics of pyroptosis, as well as exhibited decreased ATP levels and the loss of cell membrane integrity.…”

Section: Role Of Pyroptosis In Cardiac Remodelingmentioning

confidence: 99%

“…Serum GSDMD levels were also significantly higher after percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction than in age-matched stable coronary artery disease patients ( 89 ). Moreover, trimetazidine and silencing PVT1 could alleviate myocardial I/R damage through suppressing GSDMD-mediated pyroptosis in vivo and in vitro, involved TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway, improved cardiac fibrosis, inflammatory cytokines, and cardiac function ( 94 , 96 ). NLRP3 markedly promotes pyroptosis in the progression of AMI, knockdown of NLRP3 attenuated cardiomyocyte pyroptosis and significantly decreased the infarct size, as evidenced by decreased expression levels of ASC, pro-Caspase-1, Caspase-1-p10, GSDMD, cleaved GSDMD, and IL-18 ( 45 ).…”

Section: Role Of Pyroptosis In Cardiac Remodelingmentioning

confidence: 99%

“…Trimetazidine (TMZ) and Emodin increased the viability of H9c2 cardiomyocytes subjected to H/R treatment and reduced the infarct size in vivo as well as alleviated pyroptosis induced by myocardial I/R injury through the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, TMZ represents an alternative treatment for myocardial I/R injury ( 94 , 108 ). Liraglutide alleviated pyroptosis mediated by NLRP3 inflammasome by down-regulating the SIRT1/NOX4/ROS pathway in H9C2 cells ( 109 ).…”

Section: Potential Clinical Applications Of Pyroptosis To Ameliorate ...mentioning

confidence: 99%

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Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

Chai

Xue

Shi

et al. 2022

Front. Cardiovasc. Med.

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Pyroptosis is a kind of programmed cell death closely related to inflammation. The pathways that mediate pyroptosis can be divided into the Caspase-1-dependent canonical pathway and the Caspase4/5/11-dependent non-canonical pathway. The most significant difference from other cell death is that pyroptosis rapidly causes rupture of the plasma membrane, cell expansion, dissolution and rupture of the cell membrane, the release of cell contents and a large number of inflammatory factors, and send pro-inflammatory signals to adjacent cells, recruit inflammatory cells and induce inflammatory responses. Cardiac remodeling is the basic mechanism of heart failure (HF) and the core of pathophysiological research on the underlying mechanism. A large number of studies have shown that pyroptosis can cause cardiac fibrosis, cardiac hypertrophy, cardiomyocytes death, myocardial dysfunction, excessive inflammation, and cardiac remodeling. Therefore, targeting pyroptosis has a good prospect in improving cardiac remodeling in HF. In this review, the basic molecular mechanism of pyroptosis is summarized, the relationship between pyroptosis and cardiac remodeling in HF is analyzed in-depth, and the potential therapy of targeting pyroptosis to improve adverse cardiac remodeling in HF is discussed, providing some ideas for improving the study of adverse cardiac remodeling in HF.

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“…Trimetazidine alleviates MIRI-induced pyroptosis by regulating the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Moreover, a study indicated that trimetazidine could regulate pyroptosis by targeting GSDMD and playing a vital role in suppressing the expression of TLR4, MyD88, phosphorylated NF-κB p65, and NLRP3 inflammasome [ 108 ].…”

Section: Inhibition Of Pyroptosis By Drugs and Improved Mirimentioning

confidence: 99%

Research Progress on the Role of Pyroptosis in Myocardial Ischemia-Reperfusion Injury

Yang

Zhang

et al. 2022

Cells

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Myocardial ischemia-reperfusion injury (MIRI) results in the aggravation of myocardial injury caused by rapid recanalization of the ischemic myocardium. In the past few years, there is a growing interest in investigating the complex pathophysiological mechanism of MIRI for the identification of effective targets and drugs to alleviate MIRI. Currently, pyroptosis, a type of inflammatory programmed death, has received greater attention. It is involved in the MIRI development in combination with other mechanisms of MIRI, such as oxidative stress, calcium overload, necroptosis, and apoptosis, thereby forming an intertwined association between different pathways that affect MIRI by regulating common pathway molecules. This review describes the pyroptosis mechanism in MIRI and its relationship with other mechanisms, and also highlights non-coding RNAs and non-cardiomyocytes as regulators of cardiomyocyte pyroptosis by mediating associated pathways or proteins to participate in the initiation and development of MIRI. The research progress on novel small molecule drugs, clinical drugs, traditional Chinese medicine, etc. for regulating pyroptosis can play a crucial role in effective MIRI alleviation. When compared to research on other mature mechanisms, the research studies on pyroptosis in MIRI are inadequate. Although many related protective drugs have been identified, these drugs generally lack clinical applications. It is necessary to further explore and verify these drugs to expand their applications in clinical setting. Early inhibition of MIRI by targeted regulation of pyroptosis is a key concern that needs to be addressed in future studies.

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Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury

Cited by 17 publications

References 48 publications

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

Cardiac Remodeling in Heart Failure: Role of Pyroptosis and Its Therapeutic Implications

Research Progress on the Role of Pyroptosis in Myocardial Ischemia-Reperfusion Injury

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