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Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.
- Source :
-
Circulation [Circulation] 2021 Sep 21; Vol. 144 (12), pp. 947-960. Date of Electronic Publication: 2021 Jul 15. - Publication Year :
- 2021
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Cells, Cultured
Female
Humans
Induced Pluripotent Stem Cells drug effects
Induced Pluripotent Stem Cells metabolism
Isolated Heart Preparation methods
Male
Mice
Mice, Knockout
Myocardial Ischemia therapy
Myocardial Reperfusion Injury therapy
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Polymorphism, Single Nucleotide physiology
Recovery of Function drug effects
Recovery of Function physiology
Spider Venoms pharmacology
Acid Sensing Ion Channels biosynthesis
Acid Sensing Ion Channels genetics
Myocardial Ischemia genetics
Myocardial Ischemia metabolism
Myocardial Reperfusion Injury genetics
Myocardial Reperfusion Injury metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 144
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 34264749
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.121.054360