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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 build-up of acidic metabolites results in decreased intracellular and extracellular pH that can reach as low as 6.0–6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly impacts cardiac function. Methods and Results: We show that acid sensing ion channel 1a (ASIC1a) plays a key role during cardiac ischemia and demonstrate that ASIC1a is a novel therapeutic target to improve the tolerance of cardiac tissue to IRI. Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cerebrovascular ischemic injuries. Using human 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 pharmacological inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and two 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 pre- or post-conditioning 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 impact on cardiac ion channels regulating baseline electromechanical coupling and physiological performance. Conclusions: Collectively, our data provide compelling evidence for a novel pharmacological strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Myocardial Ischemia

SUBMITTER: Melanie White

LAB HEAD: Melanie White

PROVIDER: PXD024581 | Pride | 2022-11-01

REPOSITORIES: Pride

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Publications

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

Redd Meredith A MA Scheuer Sarah E SE Saez Natalie J NJ Yoshikawa Yusuke Y Chiu Han Sheng HS Gao Ling L Hicks Mark M Villanueva Jeanette E JE Joshi Yashutosh Y Chow Chun Yuen CY Cuellar-Partida Gabriel G Peart Jason N JN See Hoe Louise E LE Chen Xiaoli X Sun Yuliangzi Y Suen Jacky Y JY Hatch Robert J RJ Rollo Ben B Xia Di D Alzubaidi Mubarak A H MAH Maljevic Snezana S Quaife-Ryan Gregory A GA Hudson James E JE Porrello Enzo R ER White Melanie Y MY Cordwell Stuart J SJ Fraser John F JF Petrou Steven S Reichelt Melissa E ME Thomas Walter G WG King Glenn F GF Macdonald Peter S PS Palpant Nathan J NJ

Circulation 20210715 12

<h4>Background</h4>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.<h4>Methods</h4>We used genetic and pharmacologic methods to investigate the role ...[more]

PMID: 34264749

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Project description:The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD+STZ approach were used to generate ventricular samples (n=9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.

Dataset Information

Therapeutic inhibition of acid sensing ion channel 1a recovers heart function after ischemia-reperfusion injury

Publications

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

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