Basic Research in Cardiology

, 113:32 | Cite as

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

  • Jonathon P. AudiaEmail author
  • Xi-Ming Yang
  • Edward S. Crockett
  • Nicole Housley
  • Ehtesham Ul Haq
  • Kristen O’Donnell
  • Michael V. Cohen
  • James M. Downey
  • Diego F. AlvarezEmail author
Original Contribution


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.


Cardioprotection Caspase-1 Ischemia/reperfusion injury Myocardial infarction P2Y12 receptor antagonist VX-765 



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

Compliance with ethical standards

Conflict of interest

There are no relationships to disclose.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jonathon P. Audia
    • 1
    • 2
    Email author
  • Xi-Ming Yang
    • 3
  • Edward S. Crockett
    • 2
    • 4
  • Nicole Housley
    • 1
    • 2
  • Ehtesham Ul Haq
    • 5
  • Kristen O’Donnell
    • 4
  • Michael V. Cohen
    • 3
    • 5
  • James M. Downey
    • 3
  • Diego F. Alvarez
    • 2
    • 3
    Email author
  1. 1.Department of Microbiology and ImmunologyUniversity of South Alabama, College of MedicineMobileUSA
  2. 2.Center for Lung BiologyUniversity of South Alabama College of MedicineMobileUSA
  3. 3.Department of Physiology and Cell BiologyUniversity of South Alabama, College of MedicineMobileUSA
  4. 4.Department of PharmacologyUniversity of South Alabama, College of MedicineMobileUSA
  5. 5.Department of MedicineUniversity of South Alabama, College of MedicineMobileUSA

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