Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function

• Published in: Basic research in cardiology Vol. 113; no. 5; pp. 1 - 15
• Main Authors: Audia, Jonathon P., Yang, Xi-Ming, Crockett, Edward S., Housley, Nicole, Haq, Ehtesham Ul, O’Donnell, Kristen, Cohen, Michael V., Downey, James M., Alvarez, Diego F.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2018; Springer Nature B.V
• Subjects: Blood; Cardiology; Caspase; Caspase-1; Clinical trials; Coronary artery; Electron transport chain; Glycolysis; Heart; Heart diseases; IL-1β; Injury prevention; Ischemia; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Medical research; Medicine; Medicine & Public Health; Mitochondria; Myocardial infarction; NADH-ubiquinone oxidoreductase; Occlusion; Original Contribution; Preservation; Pyroptosis; Rats; Reperfusion; Rodents; Size reduction; Ventricle; Myocardial infarction; Cardioprotection; Ischemia/reperfusion injury; VX-765; P2Y; receptor antagonist; Caspase-1
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-018-0692-z

Patients with acute myocardial infarction receive a P2Y
12
receptor antagonist prior to reperfusion, a treatment that has reduced, but not eliminated, mortality, or heart failure. We tested whether the caspase-1 inhibitor VX-765 given at reperfusion (a requirement for clinical use) can provide sustained reduction of infarction and long-term preservation of ventricular function in a pre-clinical model of ischemia/reperfusion that had been treated with a P2Y
12
receptor antagonist. To address, the hypothesis open-chest rats were subjected to 60-min left coronary artery branch occlusion/120-min reperfusion. Vehicle or inhibitors were administered intravenously immediately before reperfusion. With vehicle only, 60.3 ± 3.8% of the risk zone suffered infarction. Ticagrelor, a P2Y
12
antagonist, and VX-765 decreased infarct size to 42.8 ± 3.3 and 29.2 ± 4.9%, respectively. Combining ticagrelor with VX-765 further decreased infarction to 17.5 ± 2.3%. Similar to recent clinical trials, combining ticagrelor and ischemic postconditioning did not result in additional cardioprotection. VX-765 plus another P2Y
12
antagonist, cangrelor, also decreased infarction and preserved ventricular function when reperfusion was increased to 3 days. In addition, VX-765 reduced infarction in blood-free, isolated rat hearts indicating at least a portion of injurious caspase-1 activation originates in cardiac tissue. While the pro-drug VX-765 only protected isolated hearts when started prior to ischemia, its active derivative VRT-043198 provided the same amount of protection when started at reperfusion, indicating that even in blood-free hearts, caspase-1 appears to exert its injury only at reperfusion. Moreover, VX-765 decreased circulating IL-1β, prevented loss of cardiac glycolytic enzymes, preserved mitochondrial complex I activity, and decreased release of lactate dehydrogenase, a marker of pyroptosis. Our results are the first demonstration of a clinical-grade drug given at reperfusion providing additional, sustained infarct size reduction when added to a P2Y
12
receptor antagonist.