The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway

PurposeProtecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC).MethodsLangendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC.ResultsVX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC.ConclusionsThe caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.

• Publication year

  2018

• Venue

  Cardiovascular Drugs and Therapy

• Publication date

  2018-03-26

• Fields of study

  Medicine

• Identifiers
  DOI 10.1007/s10557-018-6781-2PMID 29582211PMCID 5958154
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart

  2017cited by this paper
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  2017cited by this paper
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  2017cited by this paper
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  2017cited by this paper
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  2017cited by this paper
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  2014cited by this paper
• The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury.

  2013cited by this paper
• Ischemic preconditioning: Protection against myocardial necrosis and apoptosis

  2007cited by this paper
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  2006cited by this paper
• Ischemic preconditioning protects by activating prosurvival kinases at reperfusion.

  2005influential reference

• A Hidden Pathway to a Major Concern: The Role of Pyroptosis in Inducing Myocardial Infarction Reperfusion Injury and Emerging Therapeutic Targets

  2025cites this paper
• FTO controls CD8+ T cell survival and effector response by modulating m6A methylation of Fas

  2025cites this paper
• Caspases as master regulators of programmed cell death: apoptosis, pyroptosis and beyond

  2025cites this paper
• Inhibition of pyroptosis by belnacasan: A potential strategy for mitigating acute lung injury and multiple organ dysfunction.

  2025cites this paper
• Pyroptosis in cardiovascular diseases: roles, mechanisms, and clinical implications

  2025cites this paper
• Estrogen Alleviates Myocardial Ischemia–Reperfusion Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis

  2025cites this paper
• Impaired NLRP3 inflammasome signaling diverts pyroptotic to apoptotic caspase activation in macrophages

  2025cites this paper
• PANoptosis: Novel insight into regulated cell death and its potential role in cardiovascular diseases (Review)

  2024cites this paper
• Research advances in understanding the role and mechanism of pyroptosis in myocardial ischemia-reperfusion injury

  2024cites this paper
• 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

  2024cites this paper
• Myocardial Ischemia–Reperfusion Injury: Unraveling Pathophysiology, Clinical Manifestations, and Emerging Prevention Strategies

  2024cites this paper
• Preparation of VX765 sodium alginate nanogels and evaluation of their therapeutic effect via local injection on myocardial infarction in rats

  2024cites this paper
• High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction

  2024cites this paper
• Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats

  2024cites this paper
• Caspase-1 inhibition mitigates neonatal hyperoxia-induced vascular and cardiopulmonary inflammation in neonatal rats

  2024cites this paper
• Roles of pyroptosis in atherosclerosis pathogenesis.

  2023cites this paper
• The role of pyroptosis in endothelial dysfunction induced by diseases

  2023cites this paper
• VX-765 inhibits pyroptosis and reduces inflammation to prevent acute liver failure by upregulating PPARα expression.

  2023cites this paper
• Inflammation and Heart Failure: Searching for the Enemy—Reaching the Entelechy

  2023cites this paper
• Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity

  2023cites this paper
• The caspase-1 inhibitor VX765 upregulates connexin 43 expression and improves cell–cell communication after myocardial infarction via suppressing the IL-1β/p38 MAPK pathway

  2022cites this paper
• Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart

  2022cites this paper
• Research Progress on the Role of Pyroptosis in Myocardial Ischemia-Reperfusion Injury

  2022cites this paper
• Research Progress on The Mechanism and Treatment of Inflammatory Response in Myocardial Ischemia-Reperfusion Injury.

  2022cites this paper
• Pyroptosis in inflammatory diseases and cancer

  2022cites this paper
• Pyroptosis: Role and Mechanisms in Cardiovascular Disease

  2022cites this paper
• VX-765 prevents intestinal ischemia-reperfusion injury by inhibiting NLRP3 inflammasome.

  2021cites this paper
• Advanced research on the regulated necrosis mechanism in myocardial ischemia-reperfusion injury.

  2021cites this paper
• CircHelz activates NLRP3 inflammasome to promote myocardial injury by sponging miR-133a-3p in mouse ischemic heart.

  2021cites this paper
• Cannabidiol‐mediated RISK PI3K/AKT and MAPK/ERK pathways decreasing reperfusion myocardial damage

  2021cites this paper
• The Role of Pyroptosis in Ischemic and Reperfusion Injury of the Heart

  2021cites this paper
• Regulation of pyroptosis in cardiovascular pathologies: Role of noncoding RNAs

  2021cites this paper
• Pyroptosis inhibition improves the symptom of acute myocardial infarction

  2021cites this paper
• Targeting the Inflammasome in Cardiovascular Disease

  2021cites this paper
• Potential Therapies to Protect the Aging Heart Against Ischemia/Reperfusion Injury

  2021cites this paper
• CircRNA circ-NNT mediates myocardial ischemia/reperfusion injury through activating pyroptosis by sponging miR-33a-5p and regulating USP46 expression

  2021cites this paper
• VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis.

  2020cites this paper
• The importance of clinically relevant background therapy in cardioprotective studies

  2020cites this paper
• Pyroptosis: a pro-inflammatory type of cell death in cardiovascular disease.

  2020cites this paper
• Myocardial ischaemia–reperfusion injury and cardioprotection in perspective

  2020cites this paper
• Targeting the pathways of regulated necrosis: a potential strategy for alleviation of cardio-cerebrovascular injury

  2020cites this paper
• VX‐765 enhances autophagy of human umbilical cord mesenchymal stem cells against stroke‐induced apoptosis and inflammatory responses via AMPK/mTOR signaling pathway

  2020cites this paper
• Regulation of cell death in the cardiovascular system.

  2020cites this paper
• circACTR2: A Novel Mechanism Regulating High Glucose-Induced Fibrosis in Renal Tubular Cells via Pyroptosis.

  2020cites this paper
• Cardioprotective properties of the platelet P2Y12 receptor inhibitor prasugrel on cardiac ischemia/reperfusion injury

  2020cites this paper
• White spot syndrome virus infection activates Caspase 1-mediated cell death in crustacean.

  2019cites this paper
• The role of Caspase 1 in ischemia/reperfusion injury of the myocardium.

  2019cites this paper
• NLRP3 inflammasome in cardioprotective signaling.

  2019cites this paper
• Roles of pyroptosis in myocardial ischemia/reperfusion injury diseases

  2019cites this paper
• Protective effect of T3 peptide, an active fragment of tumstatin, against ischemia/reperfusion injury in rat heart.

  2019cites this paper
• Innate immunity as a target for acute cardioprotection.

  2019cites this paper
• Role of pyroptosis in cardiovascular diseases.

  2019cites this paper
• Na/K-ATPase Signaling and Cardiac Pre/Postconditioning with Cardiotonic Steroids

  2018cites this paper