Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury

Zhang, Zheng-hao; Zhang, Ziguan; Chen, Min-Wei; Yang, Ying; Li, Run-jing; Xu, Jia-jia; Yang, Cui; Li, Yu-ying; Chen, Hong-wei; Liu, Shixiao; Li, Yan-ling; Luo, Ping; Liu, Yi-jiang; Chen, Wen-bo; Zhang, Shan; Huang, Zhengrong

doi:10.1155/2022/1115749

Cited by 4 publications

(2 citation statements)

References 43 publications

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“…GSDMD activation was inhibited by GI-Y1 in the infarcted myocardium, but not in the non-infarcted tissue. The results were quite similar when GSDMD knockout mice were evaluated [150,151]. After coronary occlusions of thirty to forty-five minutes and reperfusion for 24 h, less LDH was released and the infarction was 30-60% smaller in GSDMD -/mice than in wild-type mice.…”

Section: Gasdermin D Antagonism or Genetic Modificationsupporting

confidence: 56%

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly

Cohen,

Downey

2024

IJMS

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Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.

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Section: Gasdermin D Antagonism or Genetic Modificationsupporting

confidence: 56%

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly

Cohen,

Downey

2024

IJMS

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“…For example, Zhang et al discovered that although the knockout of GSDMD conferred resistance to the heart against reperfusion injury in the acute phase of I/R, the knockout of GSDMD exacerbated reperfusion injury in the chronic phase of I/R via the activation of PARylation and the consumption of NAD+ and ATP, thus resulting in cardiomyocyte apoptosis. This study thus indicated a multidirectional role of GSDMD in I/R injury and a correlation between apoptosis and pyroptosis [ 123 ].…”

Section: Conclusion and Perspectivementioning

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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Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing

Barrère-Lemaire,

Vincent,

Jorgensen

et al. 2024

Physiological Reviews

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Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure (HF). Re-opening of the occluded artery i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits on infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (IR) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we first provide a detailed description of the cell death and inflammation mechanisms as features of IR injury, cardioprotective strategies such as ischemic postconditioning (PostC) as well as their underlying mechanisms. Due to their biological properties, the use of Mesenchymal Stromal/Stem Cells (MSC) has been considered as a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSC, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSC with enhanced properties in order to limit cell death in myocardial tissue, thereby reduce infarct size, and improve the healing phase to enhance post-infarct myocardial performance.

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Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury

Cited by 4 publications

References 43 publications

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly

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

Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing

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