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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

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Abstract

Patients with acute myocardial infarction receive a P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 receptor antagonist.

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Funding

This work was supported by the National Institutes of Health (Grant #R01HL118334 to DFA and JPA).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA

    Jonathon P. Audia & Nicole Housley

  2. Center for Lung Biology, University of South Alabama College of Medicine, Medical Sciences Building, Mobile, AL, 36688, USA

    Jonathon P. Audia, Edward S. Crockett, Nicole Housley & Diego F. Alvarez

  3. Department of Physiology and Cell Biology, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA

    Xi-Ming Yang, Michael V. Cohen, James M. Downey & Diego F. Alvarez

  4. Department of Pharmacology, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA

    Edward S. Crockett & Kristen O’Donnell

  5. Department of Medicine, University of South Alabama, College of Medicine, Mobile, AL, 36688, USA

    Ehtesham Ul Haq & Michael V. Cohen

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  1. Jonathon P. Audia
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  2. Xi-Ming Yang
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Audia, J.P., Yang, XM., Crockett, E.S. et al. 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 (2018). https://doi.org/10.1007/s00395-018-0692-z

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