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

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: We used genetic and pharmacological 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 (hiPSC-CMs) as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and post-conditioning therapeutic agents. Results: Analysis of human complex trait genetics indicate that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using hiPSC-CMs 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 (MI) 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.

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Abstract 204: HAX-1: A Novel Regulator of Energetics and Oxidative Stress in the Heart

Circulation Research ◽

10.1161/res.115.suppl_1.204 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Chi K Lam ◽

Wen Zhao ◽

Wenfeng Cai ◽

Guansheng Liu ◽

Phil Bidwell ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Calcium Handling ◽

Calcium Kinetics ◽

Atp Production ◽

Homologous Protein ◽

Induced Apoptosis ◽

Factor C

Sarcoplasmic reticulum (SR) calcium handling is central not only in the control of heart function during excitation-contraction coupling but also in mitochondrial energetics and apoptosis. Recent studies have identified the anti-apoptotic protein, HS-1 associated protein X-1 (HAX-1) as a novel regulator of SR calcium cycling. Although HAX-1 has been shown to localize to mitochondria in various tissues, we found out that it also localizes to SR through its interaction with phospholamban (PLN) in cardiac muscle. Acute or chronic overexpression of HAX-1 in cardiomyocytes promoted PLN inhibition on the calcium ATPase (SERCA) and decreased cardiomyocyte calcium kinetics and contractile parameters. Accordingly, ablation of HAX-1 significantly enhanced SERCA activity and calcium kinetics. Furthermore, the HAX-1/PLN interaction appeared to also regulate cardiomyocyte survival. Indeed, overexpression of HAX-1 and the associated depressed SR Ca-load attenuated endoplasmic reticulum stress induced apoptosis, as evidenced by reduction of both caspase-12 activation and pro-apoptotic transcription factor C/EBP homologous protein induction during ischemia/reperfusion injury. In addition, the depressed SR Ca-cycling by HAX-1 overexpression was associated with reduced mitochondrial Ca-load as reflected by: a) hyper-phosphorylation of pyruvate dehydrogenase (PDH) and decreases in its activity, to diminish ATP production consistent with the attenuated energetic demand in these hearts; and b) reduced levels of reactive oxygen species, indicating protection from oxidative damage and preserved mitochondrial integrity. These findings suggest that HAX-1 is a key regulator of Ca-cycling, apoptosis and energetics in the heart. Thus, decreases in HAX-1 levels, observed during ischemia/reperfusion injury, may contribute to the deteriorated function and progression to heart failure development.

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Inhibition of Myocardial Ischemia/Reperfusion Injury by Exosomes Secreted from Mesenchymal Stem Cells

Stem Cells International ◽

10.1155/2016/4328362 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Heng Zhang ◽

Meng Xiang ◽

Dan Meng ◽

Ning Sun ◽

Sifeng Chen

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Left Ventricle ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Heart Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Area At Risk

Exosomes secreted by mesenchymal stem cells have shown great therapeutic potential in regenerative medicine. In this study, we performed meta-analysis to assess the clinical effectiveness of using exosomes in ischemia/reperfusion injury based on the reports published between January 2000 and September 2015 and indexed in the PUBMED and Web of Science databases. The effect of exosomes on heart function was evaluated according to the following parameters: the area at risk as a percentage of the left ventricle, infarct size as a percentage of the area at risk, infarct size as a percentage of the left ventricle, left ventricular ejection fraction, left ventricular fraction shortening, end-diastolic volume, and end-systolic volume. Our analysis indicated that the currently available evidence confirmed the therapeutic potential of mesenchymal stem cell-secreted exosomes in the improvement of heart function. However, further mechanistic studies, therapeutic safety, and clinical trials are required for optimization and validation of this approach to cardiac regeneration after ischemia/reperfusion injury.

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Cardiac-Specific Expression of the Tetracycline Transactivator Confers Increased Heart Function and Survival Following Ischemia Reperfusion Injury

PLoS ONE ◽

10.1371/journal.pone.0030129 ◽

2012 ◽

Vol 7 (1) ◽

pp. e30129 ◽

Cited By ~ 5

Author(s):

Laila Elsherif ◽

Xuerong Wang ◽

Milana Grachoff ◽

Beata M. Wolska ◽

David L. Geenen ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Specific Expression ◽

Tetracycline Transactivator

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Ischemia/Reperfusion Injury and Ion Channel Blockade

Protection Against Ischemia/Reperfusion Damage of the Heart ◽

10.1007/978-4-431-68482-4_13 ◽

1998 ◽

pp. 195-214

Author(s):

Satoshi Takeo ◽

Kouichi Tanonaka ◽

Jian-Xun Liu ◽

Toru Kamiyama ◽

Itaru Ohoi ◽

...

Keyword(s):

Ion Channel ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Channel Blockade

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Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury

International Immunology ◽

10.1093/intimm/dxp051 ◽

2009 ◽

Vol 21 (7) ◽

pp. 817-829 ◽

Cited By ~ 25

Author(s):

D. Frenkel ◽

A. S. Pachori ◽

L. Zhang ◽

A. Dembinsky-Vaknin ◽

D. Farfara ◽

...

Keyword(s):

T Cell ◽

Myocardial Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Cell Responses ◽

Nasal Vaccination ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

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Helix B Surface Peptide Protects against Acute Myocardial Ischemia-Reperfusion Injury via the RISK and SAFE Pathways in a Mouse Model

Cardiology ◽

10.1159/000443680 ◽

2016 ◽

Vol 134 (2) ◽

pp. 109-117 ◽

Cited By ~ 10

Author(s):

Peng Liu ◽

Wei You ◽

Lin Lin ◽

Yongluan Lin ◽

Xiuying Tang ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Cardiomyocyte Apoptosis ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion ◽

Gsk 3Β

Objective: This study explores the effects of helix B surface peptide (HBSP) on myocardial infarct size (IS), cardiac function, cardiomyocyte apoptosis and oxidative stress damage in mouse hearts subjected to myocardial ischemia-reperfusion injury (MIRI) and also the mechanisms underlying the effects. Method: Male adult mice were subjected to 45 min of ischemia followed by 2 h of reperfusion; 5 min before the reperfusion, they were treated with HBSP or vehicle. MIRI-induced IS, cardiomyocyte apoptosis and cardiac functional impairment were determined and compared. Western blot analysis was then conducted to elucidate the mechanism of HBSP after treatment. Results: HBSP administration before reperfusion significantly reduced the myocardial IS, decreased cardiomyocyte apoptosis, reduced the activities of superoxide dismutase and malondialdehyde and partially preserved heart function. As demonstrated by the Western blot analysis, HBSP after treatment upregulated Akt/GSK-3β/ERK and STAT-3 phosphorylation; these inhibitors, in turn, weakened the beneficial effects of HBSP. Conclusion: HBSP plays a protective role in MIRI in mice by inhibiting cardiomyocyte apoptosis, reducing the MIRI-induced IS, oxidative stress and improving the heart function after MIRI. The mechanism underlying these effects of HBSP is related to the activation of the RISK (reperfusion injury salvage kinase, Akt/GSK-3β/ERK) and SAFE (STAT-3) pathways.

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Antiarrhythmic efficacy of CPUY102122, a multiple ion channel blocker, on rabbits with ischemia/reperfusion injury

Pharmacological Reports ◽

10.1016/j.pharep.2014.06.017 ◽

2014 ◽

Vol 66 (6) ◽

pp. 1022-1030

Author(s):

Minhui Wang ◽

Jiaojiao Shan ◽

Qian Yang ◽

Xianglei Ma ◽

Sisi Jin ◽

...

Keyword(s):

Ion Channel ◽

Reperfusion Injury ◽

Channel Blocker ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Antiarrhythmic Efficacy

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Cardioprotective Function of Green Rooibos (Aspalathus linearis) Extract Supplementation in Ex Vivo Ischemic Prediabetic Rat Hearts

Planta Medica ◽

10.1055/a-1239-9236 ◽

2020 ◽

Author(s):

Sybrand Engelbrecht Smit ◽

Claudine Manirafasha ◽

Erna Marais ◽

Rabia Johnson ◽

Barbara Huisamen

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Insulin Independence ◽

Rat Hearts ◽

Insulin Dependence ◽

High Caloric Diet

AbstractDiabetic patients develop ischemic heart disease and strokes more readily. Following an ischemic event, restoration of blood flow increases oxidative stress resulting in myocardial damage, termed ischemia/reperfusion injury. Aspalathus linearis (rooibos), rich in the antioxidant phenolic compound aspalathin, has been implicated as cardioprotective against ischemia/reperfusion injury with undefined mechanism in control rats. Primarily, the therapeutic potential of Afriplex green rooibos extract to prevent ischemia/reperfusion injury in cardiovascular disease-compromised rats was investigated. Additionally, Afriplex Green rooibos extractʼs cardioprotective signaling on metabolic markers and stress markers was determined using western blotting. Three hundred male Wistar rats received either 16-wk standard diet or high-caloric diet. During the final 6 wk, half received 60 mg/kg/day Afriplex green rooibos extract, containing 12.48% aspalathin. High-caloric diet increased body weight, body fat, fasting serum triglycerides, and homeostatic model assessment of insulin resistance – indicative of prediabetes. High-caloric diet rats had increased heart mass, infarct size, and decreased heart function. Afriplex green rooibos extract treatment for 6 wk lowered pre-ischemic heart rate, reduced infarct size, and improved heart function pre- and post-ischemia, without significantly affecting biometric parameters. Stabilized high-caloric diet hearts had decreased insulin independence via adenosine monophosphate activated kinase and increased inflammation (p38 mitogen-activated protein kinase), whereas Afriplex green rooibos extract treatment decreased insulin dependence (protein kinase B) and conferred anti-inflammatory effect. After 20 min ischemia, high-caloric diet hearts had upregulated ataxia–telangiectasia mutated kinase decreased insulin independence, and downregulated insulin dependence and glycogen synthase kinase 3 β inhibition. In contrast, Afriplex green rooibos extract supplementation downregulated insulin independence and inhibited extracellular signal-regulated kinase 1 and 2. During reperfusion, all protective signaling was decreased in high-caloric diet, while Afriplex green rooibos extract supplementation reduced oxidative stress (c-Jun N-terminal kinases 1 and 2) and inflammation. Taken together, Afriplex green rooibos extract supplementation for 6 wk preconditioned cardiovascular disease-compromised rat hearts against ischemia/reperfusion injury by lowering inflammation, oxidative stress, and heart rate.

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Clearance of senescent cells following cardiac ischemia-reperfusion injury improves recovery

10.1101/2020.04.28.065789 ◽

2020 ◽

Author(s):

Emily Dookun ◽

Anna Walaszczyk ◽

Rachael Redgrave ◽

Pawel Palmowski ◽

Simon Tual-Chalot ◽

...

Keyword(s):

Reperfusion Injury ◽

Cellular Senescence ◽

Ischemia Reperfusion Injury ◽

Heart Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Cardiac Ischemia ◽

Multiple Components ◽

Cell Clearance ◽

Adverse Remodeling

AbstractA key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS based proteomics reveal that biological processes associated with fibrosis and inflammation, that were increased following ischemia-reperfusion, were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of proinflammatory, profibrotic and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16 and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI senescent cells play a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.

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