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Audia 2018 Basic Res Cardiol
Additional label Labels  + , 2018-08  +
Coupling states OXPHOS  + , ET  +
Diseases Cardiovascular  +
Has abstract Patients with acute myocardial infarction
Patients with acute myocardial infarction receive a P2Y<sub>12</sub> 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<sub>12</sub> 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<sub>12</sub> 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<sub>12</sub> 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<sub>12</sub> receptor antagonist.
sub>12</sub> receptor antagonist.  +
Has editor [[Plangger M]]  +
Has info [https://www.ncbi.nlm.nih.gov/pubmed/29992382 PMID: 29992382]  +
Has publicationkeywords Cardioprotection  + , Caspase-1  + , Ischemia/reperfusion injury  + , Myocardial infarction  + , P2Y12 receptor antagonist  + , VX-765  +
Has title Audia JP, Yang XM, Crockett ES, Housley N,
Audia JP, Yang XM, Crockett ES, Housley N, Haq EU, O'Donnell K, Cohen MV, Downey JM, Alvarez DF (2018) 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. Basic Res Cardiol 113:32.
icular function. Basic Res Cardiol 113:32.  +
Instrument and method Oxygraph-2k  +
Mammal and model Rat  +
MiP area Respiration  + , Pharmacology;toxicology  +
Pathways N  + , S  + , CIV  + , NS  + , ROX  +
Preparation Permeabilized tissue  +
Stress Ischemia-reperfusion  +
Tissue and cell Heart  +
Was published by MiPNetLab US AL Mobile Winkler HH +
Was published in journal Basic Res Cardiol +
Was published in year 2018  +
Was written by Audia J + , Yang XM + , Crockett ES + , Housley N + , Haq EU + , O'Donnell K + , Cohen MV + , Downey JM + , Alvarez DF +
Categories Publications
Modification date
"Modification date" is a predefined property that corresponds to the date of the last modification of a subject and is provided by Semantic MediaWiki.
12:46:52, 30 August 2018  +
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