The Highly Selective Caspase-1 Inhibitor VX-765 Provides Additive Protection Against Myocardial Infarction in Rat Hearts When Combined With a Platelet Inhibitor

Abstract

Use of ischemic postconditioning and other related cardioprotective interventions to treat patients with acute myocardial infarction (AMI) has failed to improve outcomes in clinical trials. Because P2Y12 inhibitors are themselves postconditioning mimetics, it has been postulated that the loading dose of platelet inhibitors routinely given to patients treated for AMI masks the anti-infarct effect of other intended cardioprotective interventions. To further improve outcomes of patients with AMI, an intervention must be able to provide additive protection in the presence of a P2Y12 platelet inhibitor. Previous studies reported an anti-infarct effect using a peptide inhibitor of the pro-inflammatory caspase-1 in animal models of AMI. Herein we tested whether a pharmacologic caspase-1 inhibitor can further limit infarct size in open-chest, anesthetized rats treated with a P2Y12 inhibitor. One hour occlusion of a coronary branch followed by 2 hours of reperfusion was used to simulate clinical AMI and reflow. One group of rats received an intravenous bolus of 16 mg/kg of the highly selective caspase-1 inhibitor VX-765 30 minutes prior to onset of ischemia. A second group received a 60 μg/kg intravenous bolus of the P2Y12 inhibitor cangrelor 10 minutes prior to reperfusion followed by 6 μg/kg/min continuous infusion. A third group received treatment with both inhibitors as above. Control animals received no treatment. Infarct size was measured by tetrazolium stain and volume of muscle at risk by fluorescent microspheres. In untreated hearts, 73.7% ± 4.1% of the ischemic zone infarcted. Treatment with either cangrelor or VX-765 alone reduced infarct size to 43.8% ± 2.4% and 39.6% ± 3.6% of the ischemic zone, respectively. Combining cangrelor and VX-765 was highly protective, resulting in only 14.0% ± 2.9% infarction. The ability of VX-765 to provide protection beyond that of a platelet inhibitor alone positions it as an attractive candidate therapy to further improve outcomes in today’s patients with AMI.

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

“…In order to maximise the degree of protection in the setting of acute myocardial infarction, it is necessary to establish whether additional pharmacological approaches are able to elicit protection independent of the known phenomenon of IPC. Therefore, the potential for co-treatment with the caspase 1 inhibitor VX-765 and IPC was studied; such an approach was recently proposed and shown by Yang XM et al using VX-765 plus the antiplatelet inhibitor Cangrelor [ 6 ].…”

“…However, whether pyroptosis contributes to ischaemia-reperfusion injury has not been definitively established. The highly selective prodrug caspase 1 inhibitor, VX-765, has been shown to be protective against acute IR in vivo rat model [ 6 ]. This specific class of caspase inhibitor might be a promising possibility for future cardioprotective therapy [ 3 ].…”

Roles of pyroptosis in myocardial ischemia/reperfusion injury diseases

“…Experiments have proved that it can prevent I/R injury, and then achieve the treatment of kinase (risk) in reperfusion injury The caspase one inhibitor, VX-765, has been shown to protect the heart from acute IR injury in vivo rat model. 38 have proved that it can reduce myocardial ischemia and alleviate the risk of perfusion injury in the model. Similarly, INF4E, synthetized NLRP3 inflammasome inhibitor, can suppress the expression of a caspase-1 and cleaved IL-1βby pro-survival RISK pathway and improve the mitochondrial function.…”

Roles of pyroptosis in myocardial ischemia/reperfusion injury diseases

“…The suppression of a caspase-1 pathway may mitigate the effects of myocardial I/R injury. Experiments have proved that it can prevent I/R injury, and then achieve the treatment of kinase (risk) in reperfusion injury The caspase one inhibitor, VX-765, has been shown to protect the heart from acute IR injury in vivo rat model [38]. Furthermore, Helison et al [39] It proves that it can reduce myocardial ischemia and alleviate the risk of perfusion injury in the model.…”