Dataset Information

McDougal2017 - Metabolism in ischemic cardiomyocytes

ABSTRACT: Heart disease remains the leading cause of death globally. Although reperfusion following myocardial ischemia can prevent death by restoring nutrient flow, ischemia/reperfusion injury can cause significant heart damage. The mechanisms that drive ischemia/reperfusion injury are not well understood; currently, few methods can predict the state of the cardiac muscle cell and its metabolic conditions during ischemia. Here, we explored the energetic sustainability of cardiomyocytes, using a model for cellular metabolism to predict the levels of ATP following hypoxia. We modeled glycolytic metabolism with a system of coupled ordinary differential equations describing the individual metabolic reactions within the cardiomyocyte over time. Reduced oxygen levels and ATP consumption rates were simulated to characterize metabolite responses to ischemia. By tracking biochemical species within the cell, our model enables prediction of the cell’s condition up to the moment of reperfusion. The simulations revealed a distinct transition between energetically sustainable and unsustainable ATP concentrations for various energetic demands. Our model illustrates how even low oxygen concentrations allow the cell to perform essential functions. We found that the oxygen level required for a sustainable level of ATP increases roughly linearly with the ATP consumption rate. An extracellular O2 concentration of ~0.007 mM could supply basic energy needs in non-beating cardiomyocytes, suggesting that increased collateral circulation may provide an important source of oxygen to sustain the cardiomyocyte during extended ischemia. Our model provides a time-dependent framework for studying various intervention strategies to change the outcome of reperfusion.

SUBMITTER: Matthias Grass

PROVIDER: BIOMD0000000961 | BioModels | 2020-08-25

REPOSITORIES: BioModels

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Publications

Modeling oxygen requirements in ischemic cardiomyocytes.

McDougal Anthony D AD Dewey C Forbes CF

The Journal of biological chemistry 20170509 28

Heart disease remains the leading cause of death globally. Although reperfusion following myocardial ischemia can prevent death by restoring nutrient flow, ischemia/reperfusion injury can cause significant heart damage. The mechanisms that drive ischemia/reperfusion injury are not well understood; currently, few methods can predict the state of the cardiac muscle cell and its metabolic conditions during ischemia. Here, we explored the energetic sustainability of cardiomyocytes, using a model for ...[more]

PMID: 28487363

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Project description:- Background and Aims: Oxygen can fall to low concentrations within plant tissues, either because of environmental factors that decrease the external oxygen concentration or because the movement of oxygen through the plant tissues cannot keep pace with the rate of oxygen consumption. Recent studies document that plants can decrease their oxygen consumption in response to relative small changes in oxygen concentrations to avoid internal anoxia. The molecular mechanisms underlying this response have not been identified yet. The aim of this study was to use transcript and metabolite profiling to investigate the genomic response of Arabidopsis roots to a mild decrease in oxygen concentrations. - Methods: Arabidopsis seedlings were grown on vertical agar plates at 21, 8, 4 and 1% (v/v) external oxygen for 0.5, 2 and 48h. Roots were analyzed for changes in transcript levels using Affymetrix whole genome DNA microarrays, and for changes in metabolite levels using routine GC-MS based metabolite profiling. Root extension rates were monitored in parallel to investigate adaptive changes in growth. - Key results: Results show that root growth was inhibited and transcript and metabolite profiles were significantly altered in response to a moderate decrease in oxygen concentrations. Low oxygen leads to a preferential up-regulation of genes that might be important to trigger adaptive responses in the plant. A small but highly specific set of genes is induced very early in response to a moderate decrease in oxygen concentrations. Genes that were down-regulated mainly encoded proteins involved in energy-consuming processes. In line with this, root extension growth was significantly decreased which will ultimately save ATP and decrease oxygen consumption. This was accompanied by a differential regulation of metabolite levels at short and long term incubation at low oxygen. - Conclusions: Results show that there are adaptive changes in root extension involving large-scale reprogramming of gene expression and metabolism when oxygen concentration is decreased in a very narrow range. Experiment Overall Design: Arabidopsis seedlings were grown on vertical agar plates and treated with various oxygen concentrations (1%, 4%, 8%, and 21% as a control), 350ppm CO2 and N2 (rest) for different time periods (0.5 hours, 2 hours and 2 days. At the end of the experiment, the roots of the seedlings were immediately frozen in liquid nitrogen and used for gene expression analysis.

Dataset Information

McDougal2017 - Metabolism in ischemic cardiomyocytes

Publications

Modeling oxygen requirements in ischemic cardiomyocytes.

Similar Datasets

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