@article{f6bee83f4b284fcaafc58544bf1a19cb,
title = "Therapeutic inhibition of acid-sensing ion channel 1a recovers heart function after ischemia-reperfusion injury",
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.",
keywords = "acid sensing ion channels, acidosis, heart transplantation, ischemia, myocardial infarction",
author = "Redd, {Meredith A.} and Scheuer, {Sarah E.} and Saez, {Natalie J.} and Yusuke Yoshikawa and Chiu, {Han Sheng} and Ling Gao and Mark Hicks and Villanueva, {Jeanette E.} and Yashutosh Joshi and Chow, {Chun Yuen} and Gabriel Cuellar-Partida and Peart, {Jason N.} and {See Hoe}, {Louise E.} and Xiaoli Chen and Yuliangzi Sun and Suen, {Jacky Y.} and Hatch, {Robert J.} and Ben Rollo and Di Xia and Alzubaidi, {Mubarak A.H.} and Snezana Maljevic and Quaife-Ryan, {Gregory A.} and Hudson, {James E.} and Porrello, {Enzo R.} and White, {Melanie Y.} and Cordwell, {Stuart J.} and Fraser, {John F.} and Steven Petrou and Reichelt, {Melissa E.} and Thomas, {Walter G.} and King, {Glenn F.} and Macdonald, {Peter S.} and Palpant, {Nathan J.}",
note = "Funding Information: Financial support was provided by The University of Queensland Strategic Funding Research Initiatives (to Drs Palpant, King, Fraser, Hudson, Porrello, Reichelt, and Thomas), the Australian National Heart Foundation (grants 101889 to Dr Palpant and 199385 to Dr White), National Health and Medical Research Council Development grant (grant 2000178 to Drs Palpant, King, Macdonald, and Fraser), a UniQuest Pathfinder Award (Dr Palpant), the Whitaker International Program (scholar grant to Dr Redd), the American Australian Association (grant 441 to Dr Redd), the St Vincent{\textquoteright}s Clinic Foundation (to Dr Macdonald), the Australian National Health & Medical Research Council (program grant 1074386 to Dr Macdonald, project grant APP1085996 to Dr Thomas, and Principal Research Fellowship APP1136889 and development grant APP1158521 to Dr King), The Medical Research Future Fund (grant APP2007625 to Drs Palpant and King), and the Australian Research Council (Discovery Early Career Researcher Award DE180100976 to Dr Cuellar-Partida). Funding Information: The authors thank the Integrated Physiology Facility and the Genome Innovation Hub at The University of Queensland for technical support and assistance, and Agilent Technologies for assistance with design of gRNAs for the generation of ASIC1a knockout iPSCs. Microscopy was performed at the Institute for Molecular Bioscience Cancer Biology Imaging Facility, which was established with support from the Australian Cancer Research Foundation. Dr Redd designed, performed, and analyzed the experiments presented in , , and Figures I through V in the Data Supplement and wrote the article. Dr Scheuer designed, performed, and analyzed the experiments described in and Figure VII in the Data Supplement and wrote the article. Dr Saez produced, purified, and performed quality control analyses for peptides used in and Figures II and V through VII in the Data Supplement . Dr Yoshikawa performed myocardial infarction surgery and the echocardiography analysis presented in . Drs Gao, Hicks, Villanueva, and Joshi helped design, perform, and interpret the experiments described in and Figure VII in the Data Supplement . Dr Chow performed peptide stability experiments shown in Figure VI in the Data Supplement. Drs Reichelt, Thomas, Peart, Suen, and See Hoe conceived ideas and provided insights toward interpretation of results shown in and and Figures IV and V in the Data Supplement . Drs White and Cordwell performed, analyzed, and interpreted the proteomics study in , Figure IV in the Data Supplement , and Excel File I in the Data Supplement . H.S. Chiu and Dr Chen helped perform the experiments described in . Dr Alzubaidi helped perform the experiments described in and Figure V in the Data Supplement . Y. Sun performed the computational analysis of human translatome presented in Figure I in the Data Supplement . Dr Xia designed and characterized ASIC1a CRISPRi knockout hiPSC line used in Figure 1 and Figures II and III in the Data Supplement. Drs Hudson, Quaife-Ryan, and Porrello generated data and analyzed acid-sensing ion channel isoform expression in the mouse heart in Figure I in the Data Supplement . Dr Cuellar-Partida performed the genome-wide association studies analysis and interpretation presented in . Dr Fraser helped conceive the heart transplant studies and provided intellectual and financial support. Drs Rollo, Hatch, Maljevic, and Petrou generated and validated the acid-sensing ion channel 1a knockout mouse strain used for studies presented in and Figure IV in the Data Supplement . Dr Rollo is currently affiliated with the Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia. Dr King conceived of experimental objectives, provided intellectual and financial support, and directly supervised work related to peptide production used across all aspects of the study. Dr Macdonald conceived of experimental objectives, provided intellectual and financial support, and directly supervised work related to heart transplant modeling. Dr Palpant conceived of experimental objectives, provided intellectual and financial support, and directly supervised work related to mouse ischemia–reperfusion injury, genome-wide association studies analysis, and human pluripotent stem cell modeling, and oversaw programmatic decisions regarding study design and completion in close collaboration with Dr Macdonald and Dr King. All authors contributed to revisions and final preparation of the article. Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = sep,
doi = "10.1161/CIRCULATIONAHA.121.054360",
language = "English",
volume = "144",
pages = "947--960",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "12",
}
