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Redd MA, Scheuer SE, Saez NJ, et al. Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation. 2021;144(12):947-960doi: 10.1161/CIRCULATIONAHA.121.054360.
Redd, M. A., Scheuer, S. E., Saez, N. J., Yoshikawa, Y., Chiu, H. S., Gao, L., Hicks, M., Villanueva, J. E., Joshi, Y., Chow, C. Y., Cuellar-Partida, G., Peart, J. N., See Hoe, L. E., Chen, X., Sun, Y., Suen, J. Y., Hatch, R. J., Rollo, B., Xia, D., Alzubaidi, M. A. H., Maljevic, S., Quaife-Ryan, G. A., Hudson, J. E., Porrello, E. R., White, M. Y., Cordwell, S. J., Fraser, J. F., Petrou, S., Reichelt, M. E., Thomas, W. G., King, G. F., Macdonald, P. S., & Palpant, N. J. (2021). Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation, 144(12), 947-960. https://doi.org/10.1161/CIRCULATIONAHA.121.054360
Redd, Meredith A, et al. "Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury." Circulation vol. 144,12 (2021): 947-960. doi: https://doi.org/10.1161/CIRCULATIONAHA.121.054360
Redd MA, Scheuer SE, Saez NJ, Yoshikawa Y, Chiu HS, Gao L, Hicks M, Villanueva JE, Joshi Y, Chow CY, Cuellar-Partida G, Peart JN, See Hoe LE, Chen X, Sun Y, Suen JY, Hatch RJ, Rollo B, Xia D, Alzubaidi MAH, Maljevic S, Quaife-Ryan GA, Hudson JE, Porrello ER, White MY, Cordwell SJ, Fraser JF, Petrou S, Reichelt ME, Thomas WG, King GF, Macdonald PS, Palpant NJ. Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury. Circulation. 2021 Sep 21;144(12):947-960. doi: 10.1161/CIRCULATIONAHA.121.054360. Epub 2021 Jul 15. PMID: 34264749.
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Circulation. 2021 Sep 21;144(12):947-960. doi: 10.1161/CIRCULATIONAHA.121.054360. Epub 2021 Jul 15.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Circulation

Meredith A Redd, Sarah E Scheuer, Natalie J Saez, Yusuke Yoshikawa, Han Sheng Chiu, Ling Gao, Mark Hicks, Jeanette E Villanueva, Yashutosh Joshi, Chun Yuen Chow, Gabriel Cuellar-Partida, Jason N Peart, Louise E See Hoe, Xiaoli Chen, Yuliangzi Sun, Jacky Y Suen, Robert J Hatch, Ben Rollo, Di Xia, Mubarak A H Alzubaidi, Snezana Maljevic, Gregory A Quaife-Ryan, James E Hudson, Enzo R Porrello, Melanie Y White, Stuart J Cordwell, John F Fraser, Steven Petrou, Melissa E Reichelt, Walter G Thomas, Glenn F King, Peter S Macdonald, Nathan J Palpant

Affiliations

  1. Institute for Molecular Bioscience (M.A.R., N.J.S., H.S.C., C.Y.C., X.C., Y.S., M.A.H.A., G.F.K., N.J.P.), The University of Queensland, St Lucia, Australia.
  2. Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia (M.A.R., L.E.S.H., J.Y.S., J.F.F.).
  3. Victor Chang Cardiac Research Institute, Sydney, Australia (S.E.S., L.G., M.H., J.E.V., Y.J., P.S.M.).
  4. Cardiopulmonary Transplant Unit (S.E.S., Y.J., P.S.M.), St Vincent's Hospital, Sydney, Australia.
  5. Faculty of Medicine, University of New South Wales, Sydney, Australia (S.E.S., M.H., J.E.V., Y.J., P.S.M.).
  6. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science (N.J.S., G.F.K.), The University of Queensland, St Lucia, Australia.
  7. School of Biomedical Sciences (Y.Y., M.E.R., W.G.T.), The University of Queensland, St Lucia, Australia.
  8. Department of Pharmacology (M.H.), St Vincent's Hospital, Sydney, Australia.
  9. The University of Queensland Diamantina Institute, Faculty of Medicine and Translational Research Institute, Woolloongabba, Australia (G.C.-P.).
  10. School of Medical Science, Griffith University, Southport, Australia (J.N.P.).
  11. Faculty of Medicine, The University of Queensland, Brisbane, Australia (L.E.S.H., J.Y.S., J.F.F.).
  12. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (R.J.H., B.R., S.M., S.P.).
  13. Genome Innovation Hub (D.X.), The University of Queensland, St Lucia, Australia.
  14. QIMR Berghofer Medical Research Institute, Brisbane, Australia (G.A.Q.-R., J.E.H.).
  15. Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia (E.R.P.).
  16. Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, Australia (E.R.P.).
  17. School of Medical Sciences, School of Life and Environmental Sciences, and Charles Perkins Centre, The University of Sydney, Sydney, Australia (M.Y.W., S.J.C.).

PMID: 34264749 DOI: 10.1161/CIRCULATIONAHA.121.054360

Abstract

BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function.

METHODS: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents.

RESULTS: Analysis of human complex trait genetics indicates that variants in the

CONCLUSIONS: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Keywords: acid sensing ion channels; acidosis; heart transplantation; ischemia; myocardial infarction

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