Systems biological approaches to the cardiac signaling network

Kang, Jun Hyuk; Lee, Ho-Sung; Kang, Yun-Won; Cho, Kwang-Hyun

doi:10.1093/bib/bbv039

Cited by 10 publications

(10 citation statements)

References 107 publications

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“…In contrast to the larger number of models of short-term (milliseconds to minutes) cardiac myocyte physiology, fewer models have examined the molecular networks that control longer-term gene expression and remodelling (hours to days) 269,280 . Tavi and colleagues used a model of calcium-calmodulin-calcineurin kinetics to show that calcineurin might act as a frequency-sensitive integrator of cytosolic calcium signals 281,282 , which correlates with experimental measurements of NFAT activity, mRNA expression 281 and myocyte hypertrophy 283 .…”

Section: Systems Models Of Mechanosignallingmentioning

confidence: 99%

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

et al. 2019

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The intact heart undergoes complex and multiscale remodelling processes in response to altered mechanical cues. Remodelling of the myocardium is regulated by a combination of myocyte and non-myocyte responses to mechanosensitive pathways, which can alter gene expression and therefore function in these cells. Cellular mechanotransduction and its downstream effects on gene expression are initially compensatory mechanisms during adaptations to the altered mechanical environment, but under prolonged and abnormal loading conditions, they can become maladaptive, leading to impaired function and cardiac pathologies. In this Review, we summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. Developments in systems modelling of the networks that regulate gene expression in response to mechanical stimuli should improve integrative understanding of their roles in vivo and help to discover new combinations of drugs and device therapies targeting mechanosignalling in heart disease. Physiological and pathological cardiac structural remodelling are commonly associated with chronic alterations in haemodynamics, chamber shape and myocardial mechanics that can initially compensate for, but ultimately exacerbate, the physical triggers of cardiac remodelling 1,2. Cell-mediated mechanotrans-duction responses are important regulators of adaptive and maladaptive myocyte and matrix remodelling 3. Mechanical loading also induces the release of factors such as angiotensin II, endothelin 1 and transforming growth

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Section: Systems Models Of Mechanosignallingmentioning

confidence: 99%

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

et al. 2019

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“…We have included much “crosstalk” between various signaling cascades, but have not yet incorporated feedback loops or micro-RNA regulation. Dynamic activation of input signals and feedback loops are likely necessary to fully capture the complexities of in vivo cardiac hypertrophy and its progression to heart failure [30]. Despite these limitations, we found this network model predicts in vivo responses of cellular and organ hypertrophy and cardiac gene expression with 78% concordance.…”

Section: Discussionmentioning

confidence: 92%

“…While additional complexity in the signaling model may help to discriminate subtleties in the timing and gene expression changes and species specificity of the hypertrophy response, development of multi-scale models may be required to predict clinical phenotypes such as eccentric vs. concentric and physiologic vs. pathologic hypertrophy. Systems biology approaches to describing organ and organism level responses related to circulatory stressors will require integration of multiple phenotypic responses, such as hypertrophy signaling, apoptosis, fibrosis, and contractility, across varying time-scales using complex multi-scale modeling [30]. The ability of the hypertrophy signaling network model to predict in vivo hypertrophy of transgenic mouse models indicates that this computational model will be a strong basis for understanding multi-scale relationships between molecular regulation and organ level remodeling.…”

Section: Discussionmentioning

confidence: 99%

Network-based predictions of in vivo cardiac hypertrophy

Frank

Sutcliffe

Saucerman

2018

Journal of Molecular and Cellular Cardiology

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Cardiac hypertrophy is a common response of cardiac myocytes to stress and a predictor of heart failure. While in vitro cell culture studies have identified numerous molecular mechanisms driving hypertrophy, it is unclear to what extent these mechanisms can be integrated into a consistent framework predictive of in vivo phenotypes. To address this question, we investigate the degree to which an in vitro-based, manually curated computational model of the hypertrophy signaling network is able to predict in vivo hypertrophy of 52 cardiac-specific transgenic mice. After minor revisions motivated by in vivo literature, the model concordantly predicts the qualitative responses of 78% of output species and 69% of signaling intermediates within the network model. Analysis of four double-transgenic mouse models reveals that the computational model robustly predicts hypertrophic responses in mice subjected to multiple, simultaneous perturbations. Thus the model provides a framework with which to mechanistically integrate data from multiple laboratories and experimental systems to predict molecular regulation of cardiac hypertrophy.

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“…But, due to the substantial complexity in calcium signaling in excitable cells such as cardiomyocytes, conventional experimental approaches have limitations in understanding the CaN/NFAT signaling in these cells (Goonasekera and Molkentin 2012). Nowadays, using systems biological approaches has been covered these shortcomings to an acceptable extent and provide an apparatus to investigate complex signaling networks such as CaN/NFAT signaling (Kang et al 2016). In this regard, Fisher et al (2006) simulated the NFAT activation in T lymphocytes (T cells) and showed that NFAT activity is not sensitive to the low frequencies of Ca 2+ oscillations.…”

Section: Introductionmentioning

confidence: 99%

Ca2+-dependent calcineurin/NFAT signaling in β-adrenergic-induced cardiac hypertrophy

Khalilimeybodi

Daneshmehr²,

Kashani³

2018

gpb

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Ca2+ is an important mediator in the β-adrenergic-induced cardiac hypertrophy. The β-adrenergic stimulation alters the Ca2+ transient characteristics including its oscillation frequency, diastolic and systolic levels which lead to the CaN activation and subsequent NFAT-dependent hypertrophic genes transcription. Moreover, β-adrenergic-induced alterations in PKA and GSK3β kinase activities in both the cytosol and the nucleus regulate NFAT nuclear translocation and contribute in its hypertrophic response. Due to the complex nature of CaN/NFAT signaling in cardiac cells, we use a computational approach to investigate the β-adrenergic-induced CaN/NFAT activation in the cardiac myocytes. The presented model predicts well the main physiological characteristics of CaN/NFAT signaling in accordance with the experimental observations. The presented model establishes the previous experimental and mathematical results on the principal role of Ca2+ oscillation frequency in the CaN/NFAT signaling and shows that increase in Ca2+ oscillation frequency enhances CaN activity and its sensitivity to low ISO concentrations. The model illustrates that in addition to the known ISO effect on Ca2+ transient amplitude, ISO-induced alterations in Ca2+ oscillation frequency, PKA and GSK3β kinase activities also greatly affect the β-adrenergic-induced NFAT activity. We also found that PKA has both pro-hypertrophic and anti-hypertrophic effects on NFAT activation and is the main kinase in ISO-induced NFAT activation.

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Systems biological approaches to the cardiac signaling network

Cited by 10 publications

References 107 publications

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

Network-based predictions of in vivo cardiac hypertrophy

Ca2+-dependent calcineurin/NFAT signaling in β-adrenergic-induced cardiac hypertrophy

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