Enhanced activity and subcellular redistribution of myocardial hexokinase after acute myocardial infarction

Yeih, Dong Feng; Yeh, Hung I.; Lin, Lian‐Yu; Tsay, Yeou Guang; Chiang, Fu-Tien; Tseng, Chuen Den; Tseng, Yung Zu

doi:10.1016/j.ijcard.2009.12.002

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…The mechanism of HK detachment from the mitochondria during ischaemia is, at least partly, related to acidification and increases in G6P (Pasdois et al, 2013). The endogenous adaptation following ischaemia in cardiac tissue is associated with increases (∼30-70%) in total and mitochondrial HK (McFalls et al, 2002;Miyamoto et al, 2010;Wu et al, 2011;Yeih et al, 2011). Large increases (200-300%) in HK activity were also observed in regenerated skeletal muscle 2 weeks after the IR insult (Smeele et al, 2012).…”

Section: Ir Post-myocardial Infarction Regenerationmentioning

confidence: 99%

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Nederlof

Eerbeek

Hollmann

et al. 2014

British J Pharmacology

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Mitochondrially bound hexokinase II (mtHKII) has long been known to confer cancer cells with their resilience against cell death. More recently, mtHKII has emerged as a powerful protector against cardiac cell death. mtHKII protects against ischaemia‐reperfusion (IR) injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end‐effectors through which ischaemic preconditioning protects against myocardial IR injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated outer mitochondrial membrane (OMM) permeability during ischaemia and reperfusion resulting in stabilization of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced reactive oxygen species production. Increasing mtHK may also have important metabolic consequences, such as improvement of glucose‐induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of HKII may contribute to the altered sensitivity of diabetes to cardiac ischaemic diseases. The interaction of HKII with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge now is to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischaemic preconditioning, metformin administration and miR‐155/miR‐144 manipulations are potential means of doing just that. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

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Section: Ir Post-myocardial Infarction Regenerationmentioning

confidence: 99%

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Nederlof

Eerbeek

Hollmann

et al. 2014

British J Pharmacology

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“…Upon reperfusion after a period of ischemia, the activity of HK is increased in both the cytosolic and mitochondrial compartments [50], probably promoted by activation of Akt signaling via the RISK pathway. Under these conditions of Akt-enhanced HK2 binding to mitochondria, the heart is in a cardioprotected state.…”

Section: Regulation Of Glucose Metabolism By Hk During I/rmentioning

confidence: 99%

Hexokinases and cardioprotection

Calmettes¹,

Ribalet²,

John³

et al. 2015

Journal of Molecular and Cellular Cardiology

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As mediators of the first enzymatic step in glucose metabolism, hexokinases (HKs) orchestrate a variety of catabolic and anabolic uses of glucose, regulate antioxidant power by generating NADPH for glutathione reduction, and modulate cell death processes by directly interacting with the voltage-dependent anion channel (VDAC), a regulatory component of the mitochondrial permeability transition pore (mPTP). Here we summarize the current state-of-knowledge about HKs and their role in protecting the heart from ischemia/reperfusion (I/R) injury, reviewing: 1) the properties of different HK isoforms and how their function is regulated by their subcellular localization; 2) how HKs modulate glucose metabolism and energy production during I/R; 3) the molecular mechanisms by which HKs influence mPTP opening and cellular injury during I/R; 4) how different metabolic and HK profiles correlate with susceptibility to I/R injury and cardioprotective efficacy in cancer cells, neonatal hearts, and normal, hypertrophied and failing adult hearts, and how these difference may guide novel therapeutic strategies to limit I/R injury in the heart.

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“…HK2 encodes the first key enzyme in the glycolytic pathway; enzyme that phosphorylates glucose to glucose-6-phosphate (G6P) [ 18 ]. Studies have shown that increased HK2 activity after AMI is correlated with oxidative stress and increased left ventricular end-diastolic volume suggesting that HK2 may be involved in post-AMI heart failure [ 19 ]. Phosphofructokinase 1 ( PFK-1 ) is responsible for the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub glycolysis-related genes in acute myocardial infarction and their correlation with immune infiltration using bioinformatics analysis

Zhang,

Gao

et al. 2024

BMC Cardiovasc Disord

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Purpose Glycolysis and immune metabolism play important roles in acute myocardial infarction (AMI). Therefore, this study aimed to identify and experimentally validate the glycolysis-related hub genes in AMI as diagnostic biomarkers, and further explore the association between hub genes and immune infiltration. Methods Differentially expressed genes (DEGs) from AMI peripheral blood mononuclear cells (PBMCs) were analyzed using R software. Glycolysis-related DEGs (GRDEGs) were identified and analyzed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) for functional enrichment. A protein–protein interaction network was constructed using the STRING database and visualized using Cytoscape software. Immune infiltration analysis between patients with AMI and stable coronary artery disease (SCAD) controls was performed using CIBERSORT, and correlation analysis between GRDEGs and immune cell infiltration was performed. We also plotted nomograms and receiver operating characteristic (ROC) curves to assess the predictive accuracy of GRDEGs for AMI occurrence. Finally, key genes were experimentally validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting using PBMCs. Results A total of 132 GRDEGs and 56 GRDEGs were identified on the first day and 4–6 days after AMI, respectively. Enrichment analysis indicated that these GRDEGs were mainly clustered in the glycolysis/gluconeogenesis and metabolic pathways. Five hub genes (HK2, PFKL, PKM, G6PD, and ALDOA) were selected using the cytoHubba plugin. The link between immune cells and hub genes indicated that HK2, PFKL, PKM, and ALDOA were significantly positively correlated with monocytes and neutrophils, whereas G6PD was significantly positively correlated with neutrophils. The calibration curve, decision curve analysis, and ROC curves indicated that the five hub GRDEGs exhibited high predictive value for AMI. Furthermore, the five hub GRDEGs were validated by RT-qPCR and western blotting. Conclusion We concluded that HK2, PFKL, PKM, G6PD, and ALDOA are hub GRDEGs in AMI and play important roles in AMI progression. This study provides a novel potential immunotherapeutic method for the treatment of AMI.

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Enhanced activity and subcellular redistribution of myocardial hexokinase after acute myocardial infarction

Cited by 6 publications

References 30 publications

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Hexokinases and cardioprotection

Identification of hub glycolysis-related genes in acute myocardial infarction and their correlation with immune infiltration using bioinformatics analysis

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