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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. Audia
  • Xi-Ming Yang
  • Edward S. Crockett
  • Nicole Housley
  • Ehtesham Ul Haq
  • Kristen O’Donnell
  • Michael V. Cohen
  • James M. Downey
  • Diego F. Alvarez
Original Contribution
  • 226 Downloads

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.

Keywords

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

Notes

Funding

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.

References

  1. 1.
    Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, Biondi-Zoccai GG, Houser JE, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, Dobrina A (2008) Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117:2670–2683.  https://doi.org/10.1161/CIRCULATIONAHA.107.740233 CrossRefPubMedGoogle Scholar
  2. 2.
    Alvarez DF, Housley N, Koloteva A, Zhou C, O’Donnell K, Audia JP (2016) Caspase-1 activation protects lung endothelial barrier function during infection-induced stress. Am J Respir Cell Mol Biol 55:500–510.  https://doi.org/10.1165/rcmb.2015-0386OC CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Audia JP, Lindsey AS, Housley NA, Ochoa CR, Zhou C, Toba M, Oka M, Annamdevula NS, Fitzgerald MS, Frank DW, Alvarez DF (2013) In the absence of effector proteins, the Pseudomonas aeruginosa type three secretion system needle tip complex contributes to lung injury and systemic inflammatory responses. PLoS One 8:e81792.  https://doi.org/10.1371/journal.pone.0081792 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Barrabes JA, Inserte J, Mirabet M, Quiroga A, Hernando V, Figueras J, Garcia-Dorado D (2010) Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 104:128–135.  https://doi.org/10.1160/TH09-07-0440 CrossRefPubMedGoogle Scholar
  5. 5.
    Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM, Yellon DM (2015) Cardioprotective properties of the platelet P2Y12 receptor inhibitor, cangrelor: protective in diabetics and reliant upon the presence of blood. Cardiovasc Drugs Ther 29:415–418.  https://doi.org/10.1007/s10557-015-6609-2 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515:431–435.  https://doi.org/10.1038/nature13909 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cohen MV, Downey JM (2017) The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions. Basic Res Cardiol 112:64.  https://doi.org/10.1007/s00395-017-0653-y CrossRefPubMedGoogle Scholar
  8. 8.
    Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guerin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F, Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Rande JL, Unterseeh T, Le Breton H, Beard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M (2015) Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 373:1021–1031.  https://doi.org/10.1056/NEJMoa1505489 CrossRefPubMedGoogle Scholar
  9. 9.
    Engstrom T, Kelbaek H, Helqvist S, Hofsten DE, Klovgaard L, Clemmensen P, Holmvang L, Jorgensen E, Pedersen F, Saunamaki K, Ravkilde J, Tilsted HH, Villadsen A, Aaroe J, Jensen SE, Raungaard B, Botker HE, Terkelsen CJ, Maeng M, Kaltoft A, Krusell LR, Jensen LO, Veien KT, Kofoed KF, Torp-Pedersen C, Kyhl K, Nepper-Christensen L, Treiman M, Vejlstrup N, Ahtarovski K, Lonborg J, Kober L, Third Danish study of optimal acute treatment of patients With STEMI-IPI (2017) Effect of Ischemic postconditioning during primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2:490–497.  https://doi.org/10.1001/jamacardio.2017.0022 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Favaretto E, Roffi M, Frigo AC, Lee MS, Marra MP, Napodano M, Tarantini G (2014) Meta-analysis of randomized trials of postconditioning in ST-elevation myocardial infarction. Am J Cardiol 114:946–952.  https://doi.org/10.1016/j.amjcard.2014.06.026 CrossRefPubMedGoogle Scholar
  11. 11.
    Frantz S, Ducharme A, Sawyer D, Rohde LE, Kobzik L, Fukazawa R, Tracey D, Allen H, Lee RT, Kelly RA (2003) Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol 35:685–694.  https://doi.org/10.1016/S0022-2828(03)00113-5 CrossRefPubMedGoogle Scholar
  12. 12.
    Fröhlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ (2013) Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 34:1714–1722.  https://doi.org/10.1093/eurheartj/eht090 CrossRefPubMedGoogle Scholar
  13. 13.
    Fujii T, Tamura M, Tanaka S, Kato Y, Yamamoto H, Mizushina Y, Shiroishi T (2008) Gasdermin D (Gsdmd) is dispensable for mouse intestinal epithelium development. Genesis 46:418–423.  https://doi.org/10.1002/dvg.20412 CrossRefPubMedGoogle Scholar
  14. 14.
    Hausenloy DJ, Botker HE, Engstrom T, Erlinge D, Heusch G, Ibanez B, Kloner RA, Ovize M, Yellon DM, Garcia-Dorado D (2017) Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J 38:935–941.  https://doi.org/10.1093/eurheartj/ehw145 PubMedGoogle Scholar
  15. 15.
    Hausenloy DJ, Garcia-Dorado D, Botker HE, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JPG, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, Ferdinandy P (2017) Novel targets and future strategies for acute cardioprotection: position paper of the European society of cardiology working group on cellular biology of the heart. Cardiovasc Res 113:564–585.  https://doi.org/10.1093/cvr/cvx049 CrossRefPubMedGoogle Scholar
  16. 16.
    Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784.  https://doi.org/10.1093/eurheartj/ehw224 PubMedGoogle Scholar
  17. 17.
    Heusch G, Rassaf T (2016) Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 119:676–695.  https://doi.org/10.1161/CIRCRESAHA.116.308736 CrossRefPubMedGoogle Scholar
  18. 18.
    Holly TA, Drincic A, Byun Y, Nakamura S, Harris K, Klocke FJ, Cryns VL (1999) Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivo. J Mol Cell Cardiol 31:1709–1715.  https://doi.org/10.1006/jmcc.1999.1006 CrossRefPubMedGoogle Scholar
  19. 19.
    Ibáñez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1454–1471.  https://doi.org/10.1016/j.jacc.2015.02.032 CrossRefPubMedGoogle Scholar
  20. 20.
    Jong WM, Leemans JC, Weber NC, Juffermans NP, Schultz MJ, Hollmann MW, Zuurbier CJ (2014) Nlrp3 plays no role in acute cardiac infarction due to low cardiac expression. Int J Cardiol 177:41–43.  https://doi.org/10.1016/j.ijcard.2014.09.148 CrossRefPubMedGoogle Scholar
  21. 21.
    Kaufman R (Last updated December 3, 2007) Phase 2 clinical study in psoriasis with oral investigational drug VX-765. ClinicalTrials.gov Web site: https://clinicaltrials.gov/ct2/show/NCT00205465. Accessed 5 Oct 2017
  22. 22.
    Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123:594–604.  https://doi.org/10.1161/CIRCULATIONAHA.110.982777 CrossRefPubMedGoogle Scholar
  23. 23.
    Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671.  https://doi.org/10.1038/nature15541 CrossRefPubMedGoogle Scholar
  24. 24.
    Man SM, Kanneganti TD (2015) Regulation of inflammasome activation. Immunol Rev 265:6–21.  https://doi.org/10.1111/imr.12296 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-1b. Mol Cell 10:417–426.  https://doi.org/10.1016/S1097-2765(02)00599-3 CrossRefPubMedGoogle Scholar
  26. 26.
    Mastrocola R, Penna C, Tullio F, Femminó S, Nigro D, Chiazza F, Serpe L, Collotta D, Alloatti G, Cocco M, Bertinaria M, Pagliaro P, Aragno M, Collino M (2016) Pharmacological inhibition of NLRP3 inflammasome attenuates myocardial ischemia/reperfusion injury by activation of RISK and mitochondrial pathways. Oxid Med Cell Longev 2016:11.  https://doi.org/10.1155/2016/5271251 Google Scholar
  27. 27.
    Mitra S, Wewers MD, Sarkar A (2015) Mononuclear phagocyte-derived microparticulate caspase-1 induces pulmonary vascular endothelial cell injury. PLoS One 10:e0145607.  https://doi.org/10.1371/journal.pone.0145607 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mocanu MM, Baxter GF, Yellon DM (2000) Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury. Br J Pharmacol 130:197–200.  https://doi.org/10.1038/sj.bjp.0703336 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    National Research Council (2011) Guide for the care and use of laboratory animals, vol 8. The National Academies Press, Washington.  https://doi.org/10.17226/12910 Google Scholar
  30. 30.
    Pesta D, Gnaiger E (2012) High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810:25–58.  https://doi.org/10.1007/978-1-61779-382-0_3 CrossRefPubMedGoogle Scholar
  31. 31.
    Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA (2001) Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1b. Proc Natl Acad Sci USA 98:2871–2876.  https://doi.org/10.1073/pnas.041611398 CrossRefPubMedGoogle Scholar
  32. 32.
    Sandanger O, Gao E, Ranheim T, Bliksoen M, Kaasboll OJ, Alfsnes K, Nymo SH, Rashidi A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A (2016) NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun 469:1012–1020.  https://doi.org/10.1016/j.bbrc.2015.12.051 CrossRefPubMedGoogle Scholar
  33. 33.
    Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M (2007) The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J Biol Chem 282:36321–36329.  https://doi.org/10.1074/jbc.M708182200 CrossRefPubMedGoogle Scholar
  34. 34.
    Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665.  https://doi.org/10.1038/nature15514 CrossRefPubMedGoogle Scholar
  35. 35.
    Syed FM, Hahn HS, Odley A, Guo Y, Vallejo JG, Lynch RA, Mann DL, Bolli R, Dorn GW (2005) Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia. Circ Res 96:1103–1109.  https://doi.org/10.1161/01.RES.0000166925.45995.ed CrossRefPubMedGoogle Scholar
  36. 36.
    van Hout GPJ, Bosch L, Ellenbroek GH, de Haan JJ, van Solinge WW, Cooper MA, Arslan F, de Jager SC, Robertson AA, Pasterkamp G, Hoefer IE (2016) The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J.  https://doi.org/10.1093/eurheartj/ehw247 Google Scholar
  37. 37.
    Vilahur G, Gutiérrez M, Casani L, Varela L, Capdevila A, Pons-Lladó G, Carreras F, Carlsson L, Hidalgo A, Badimon L (2016) Protective effects of ticagrelor on myocardial injury after infarction. Circulation 134:1708–1719.  https://doi.org/10.1161/CIRCULATIONAHA.116.024014 CrossRefPubMedGoogle Scholar
  38. 38.
    Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC (2007) (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1b and IL-18. J Pharmacol Exp Ther 321:509–516.  https://doi.org/10.1124/jpet.106.111344 CrossRefPubMedGoogle Scholar
  39. 39.
    Yang XM, Cui L, Alhammouri A, Downey JM, Cohen MV (2013) Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther 27:403–412.  https://doi.org/10.1007/s10557-013-6474-9 CrossRefPubMedGoogle Scholar
  40. 40.
    Yang XM, Downey JM, Cohen MV, Housley NA, Alvarez DF, Audia JP (2017) The highly selective caspase-1 inhibitor VX-765 provides additive protection against myocardial infarction in rat hearts when combined with a platelet inhibitor. J Cardiovasc Pharmacol Ther 22:574–578.  https://doi.org/10.1177/1074248417702890 CrossRefPubMedGoogle Scholar
  41. 41.
    Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV (2013) Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 18:251–262.  https://doi.org/10.1177/1074248412467692 CrossRefPubMedGoogle Scholar
  42. 42.
    Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y (2015) Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 35:1805–1814.  https://doi.org/10.1161/atvbaha.115.305655 CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Jonathon P. Audia
    • 1
    • 2
  • 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
  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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