Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia–Reperfusion Injury-Reference-Cited by-同舟云学术

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

Published:2021-09-21 Issue:12 Volume:144 Page:947-960
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Redd Meredith A.¹²^ORCID,Scheuer Sarah E.³⁴⁵,Saez Natalie J.¹⁶,Yoshikawa Yusuke⁷,Chiu Han Sheng¹,Gao Ling³,Hicks Mark³⁸⁵,Villanueva Jeanette E.³⁵,Joshi Yashutosh³⁴⁵^ORCID,Chow Chun Yuen¹^ORCID,Cuellar-Partida Gabriel⁹,Peart Jason N.¹⁰,See Hoe Louise E.²¹¹,Chen Xiaoli¹,Sun Yuliangzi¹^ORCID,Suen Jacky Y.²¹¹^ORCID,Hatch Robert J.¹²^ORCID,Rollo Ben¹²,Xia Di¹³^ORCID,Alzubaidi Mubarak A.H.¹,Maljevic Snezana¹²,Quaife-Ryan Gregory A.¹⁴^ORCID,Hudson James E.¹⁴,Porrello Enzo R.¹⁵¹⁶^ORCID,White Melanie Y.¹⁷,Cordwell Stuart J.¹⁷,Fraser John F.²¹¹,Petrou Steven¹²,Reichelt Melissa E.⁷,Thomas Walter G.⁷,King Glenn F.¹⁶^ORCID,Macdonald Peter S.³⁴⁵^ORCID,Palpant Nathan J.¹^ORCID

Affiliation:

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.).

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 ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell–derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.121.054360

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