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Acid Sensing Ion Channel 1A Is a Key Mediator of Cardiac Ischemia-Reperfusion Injury Meredith A

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Acid Sensing Ion Channel 1A Is a Key Mediator of Cardiac Ischemia-Reperfusion Injury Meredith A bioRxiv preprint doi: https://doi.org/10.1101/869826; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury Meredith A. Redd1,9,15, Sarah E. Scheuer2,3,4,15, Natalie J. Saez1, Ling Gao2, Mark Hicks2,4,5, Jeanette E. Villanueva2,4, Melissa E. Reichelt6, Jason N. Peart7, Louise E. See Hoe8,9, Han S. Chiu1, Xiaoli Chen1, Yuliangzi Sun1, Jacky Y. Suen8,9, Robert J Hatch10, Ben Rollo10, Mubarak A,H. Alzubaidi1, Snezana Maljevic10, Greg A. Quaife-Ryan11, Walter G. Thomas6, James E. Hudson11, Enzo R. Porrello12,13, Gabriel Cuellar-Partida14, John F. Fraser8,9, Steven Petrou10, Glenn F. King1,16, Peter S. Macdonald2,3,4,16 & Nathan J. Palpant1,16 1Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia 2Victor Chang Cardiac Research Institute, Sydney, Australia 3Cardiopulmonary Transplant Unit, St. Vincent’s Hospital, Sydney, Australia 4Faculty of Medicine, University of New South Wales, Sydney, Australia 5Department of Pharmacology, St. Vincent’s Hospital, Sydney, Australia 6School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia 7School of Medical Science, Griffith University, Southport, Australia 8Faculty of Medicine, The University of Queensland, Brisbane, Australia 9Critical Care Research Group, The Prince Charles Hospital and The University of Queensland, Brisbane, Australia 10Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia 11QIMR Berghofer Medical Research Institute, Brisbane, Australia 12Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Australia 13Department of Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, Australia 14The University of Queensland Diamantina Institute, Faculty of Medicine and Translational Research Institute, Woolloongabba, Australia 15These authors contributed equally 16Corresponding authors Addresses for correspondence: Dr. Nathan J. Palpant Institute for Molecular Bioscience 306 Carmody Road, Building 80 (Level 4 North) St. Lucia, Queensland, Australia, 4072 T: +61 7 3346 2054; E: [email protected] Professor Glenn F. King Institute for Molecular Bioscience 306 Carmody Road, Building 80 (Level 2 North) St. Lucia, Queensland, Australia, 4072 T: +61 7 3346 2025; E: [email protected] Professor Peter Macdonald Cardiopulmonary Transplant Unit, St. Vincent’s Hospital Darlinghurst, New South Wales, Australia T: +61 2 8382 2641; E: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/869826; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract The proton-gated acid-sensing ion channel 1a (ASIC1a) is implicated in the injury response to cerebral ischemia but little is known about its role in cardiac ischemia. We provide genetic evidence that ASIC1a is involved in myocardial ischemia-reperfusion injury (IRI) and show that pharmacological inhibition of ASIC1a yields robust cardioprotection in rodent and human models of cardiac ischemia, resulting in improved post-IRI cardiac viability and function. Consistent with a key role for ASIC1a in cardiac ischemia, we show that polymorphisms in the ASIC1 genetic locus are strongly associated with myocardial infarction. Collectively, our data provide compelling evidence that ASIC1a is a key target for cardioprotective drugs to reduce the burden of disease associated with myocardial ischemia. 2 bioRxiv preprint doi: https://doi.org/10.1101/869826; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Introduction Conditions caused by obstruction of blood flow to the heart, such as myocardial infarction (MI), are the most common emergency manifestation of cardiovascular disease1. Although acute reperfusion therapies have improved patient outcomes, mortality remains high2 and MI is one of the largest attributable risks for heart failure (HF)3. Globally, 1 in 5 people develop HF, with annual healthcare costs of $108B4,5. Heart transplantation remains the most effective treatment option for HF6,7, but 75% of potential donor hearts are discarded, many due to sensitivity of the donor heart to ischemic injury8. Myocardial sensitivity to ischemia-reperfusion injury (IRI) therefore remains a primary point of vulnerability underlying cardiovascular disease, which is the leading cause of morbidity and mortality worldwide9. Despite decades of preclinical therapeutic development, there are currently no drugs that block the acute injury response to cardiac ischemia10. Myocardial IRI is a complex pathophysiological process that underlies the cardiac injury sustained during cardiac surgery, heart transplant, MI, and cardiac arrest. During myocardial ischemia, reduced oxygen availability causes a shift from fatty acid metabolism to anaerobic glycolysis11,12. The resulting lactic acidosis causes the extracellular pH to fall to as low as 6.0– 6.513,14. In patients suffering from acute MI, the severity of acidosis strongly correlates with patient mortality, with pH < 7.35 associated with > 60% mortality15. Ongoing acidosis results in the activation of several transmembrane ion channels and receptors, including the sodium-hydrogen exchanger (NHE), glutamate-gated NMDA receptors, and TRP family of ion channels, each of which are thought to contribute to calcium overload, metabolic dysfunction, and eventually cell death16-18. In line with this, the Expedition Trial showed significant protection against peri-operative MI with the NHE inhibitor, cariporide, in patients undergoing high-risk coronary artery bypass surgery19. While this trial failed due to cerebrovascular complications, it demonstrated that pharmacological conditioning has the capacity to reduce the injury response to myocardial IRI. Acid sensing ion channels (ASICs) are voltage-independent proton-gated cation channels of the degenerin/epithelial sodium channel superfamily20. There are six ASIC isoforms derived from four genes (ACCN1–4), which assemble into homotrimeric or heterotrimeric channels. The pH sensitivity and kinetics of ASICs are determined by their subunit composition21,22. ASICs are involved in extracellular acidification-induced calcium overload in neurons and cardiomyocytes23-25. ASIC1a, a splice variant of the ACCN1 gene, is the most pH-sensitive ASIC channel. Activation begins at pH ≤ 7, with half-maximal activation at pH 6.626,27, and ASIC1a currents are potentiated by numerous metabolic events that 3 bioRxiv preprint doi: https://doi.org/10.1101/869826; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. occur during ischemia including membrane stretch and increased levels of extracellular lactate, pyruvate, and arachidonic acid28,29. ASIC1a plays a critical role in mediating neuronal death after cerebral ischemia, and inhibition of ASIC1a through genetic ablation or pharmacological blockade is neuroprotective in rodent models of ischemic stroke30-32. In this study, we used genetic and pharmacological approaches to demonstrate, for the first time, that ASIC1a is a critical mediator of the injury response to myocardial IRI. We show that venom-derived inhibitors of ASIC1a provide robust cardioprotection across multiple species and model systems from the cellular to whole-organ level, including models of IRI and donor heart preservation. Taken together, our data provide compelling evidence that ASIC1a is an important target for cardioprotective drugs, with potential application in the treatment of MI, cardiac arrest, and the preservation of donor hearts. Results Genetic ablation of ASIC1a improves functional recovery following cardiac IRI. We assessed ASIC isoform expression in the adult mouse heart from transcriptomic data of sorted cardiac cell populations after sham and myocardial infarction (MI)33. In sham hearts, ASIC1 expression was highest in cardiomyocytes, while endothelial cells and fibroblasts expressed both ASIC1 and ASIC3. In all three cell types, ASIC4 and ASIC2 had low and undetectable expression, respectively (Fig. 1a). ASIC1 was not differentially expressed between sham and post-MI conditions in cardiomyocytes or endothelial cells (Supplementary Fig. 1a). ASIC1 encodes two isoforms from the same genetic locus, ASIC1a and ASIC1b, that are genetically conserved among bilateria. As opposed to ASIC1b, which is primarily involved in nociception34, we focused on ASIC1a due to its known role in mediating injury responses resulting from ischemia in the brain22. We subsequently tested whether ASIC1a governs the response to cardiac ischemic injury. To determine whether ASIC1a plays a functional role during cardiac ischemia,
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