An Integrated Mathematical Model of Thrombin-, Histamine-and VEGF-Mediated Signalling in Endothelial Permeability

Wang, Xiaona; Han, Bu-Cong; Zhang, Jingxian; Liu, X. H.; Tan, Chunyan; Jiang, Yuyang; Low, Boon Chuan; Tidor, Bruce; Chen, Yu Zong

doi:10.1186/1752-0509-5-112

Cited by 17 publications

(9 citation statements)

References 101 publications

(127 reference statements)

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“…Moreover, we distinguished an acute presence of inter endothelial gaps suggesting an H 2 O 2 -mediated retraction of the cells. We also noticed the same typical morphological pattern with histamine treatment, a potent inducer of endothelial and vascular permeability [32]. Based on these findings, the H 2 O 2 and histamine-mediated changes in the organization of actin seem to be a fast and strong response that contributes to increase stress resistance.…”

Section: Discussionsupporting

confidence: 67%

Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation

2012

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BackgroundLoss of endothelial cell integrity and selective permeability barrier is an early event in the sequence of oxidant-mediated injury and may result in atherosclerosis, hypertension and facilitation of transendothelial migration of cancer cells during metastasis. We already reported that endothelial cell integrity is tightly regulated by the balanced co-activation of p38 and ERK pathways. In particular, we showed that phosphorylation of tropomyosin-1 (tropomyosin alpha-1 chain = Tm1) at Ser283 by DAP kinase, downstream of the ERK pathway might be a key event required to maintain the integrity and normal functions of the endothelium in response to oxidative stress.MethodsEndothelial permeability was assayed by monitoring the passage of Dextran-FITC through a tight monolayer of HUVECs grown to confluence in Boyden chambers. Actin and Tm1 dynamics and distribution were evaluated by immunofluorescence. We modulated the expression of Tm1 by siRNA and lentiviral-mediated expression of wild type and mutated forms of Tm1 insensitive to the siRNA. Transendothelial migration of HT-29 colon cancer cells was monitored in Boyden chambers similarly as for permeability.ResultsWe provide evidence indicating that Tm1 phosphorylation at Ser283 is essential to regulate endothelial permeability under oxidative stress by modulating actin dynamics. Moreover, the transendothelial migration of colon cancer cells is also regulated by the phosphorylation of Tm1 at Ser283.ConclusionOur finding strongly support the role for the phosphorylation of endothelial Tm1 at Ser283 to prevent endothelial barrier dysfunction associated with oxidative stress injury.

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Section: Discussionsupporting

confidence: 67%

Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation

2012

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“…Previous reports showed that glycerophosphatidylcholine concentration typically increases with age; moreover, this increase is more pronounced in aged AD patients and those with enhanced A ␤ plaque formation (29)(30)(31)(32). Breakdown of APP and aggregation of amyloid plaques are the major causes of neuronal deterioration in AD.…”

Section: Discussionmentioning

confidence: 99%

Global changes of phospholipids identified by MALDI imaging mass spectrometry in a mouse model of Alzheimer's disease

Hong

Kang

Kim

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org Several hypotheses regarding the cause of AD have been proposed, among which the amyloid hypothesis is the most widely accepted ( 2 ). According to this hypothesis, AD is caused by abnormal accumulation of misfolded ␤ -amyloid (A ␤ ), a sequential cleavage product produced from amyloid precursor protein (APP) by ␤ -and ␥ -secretases, and hyperphosphorylated tau protein. Several lines of evidence support the idea that A ␤ can trigger the hyperphosphorylation of tau, resulting in neuronal degeneration in the brain ( 3, 4 ).There is evidence that FFAs are associated with several signaling processes related to the pathogenesis of AD. In particular, palmitic and stearic acid induce AD by triggering hyperphosphorylation of tau protein ( 5 ). Membrane phospholipids (PLs) are a prominent source of FFAs. Under disease conditions, phospholipase enzymes are produced in excess, inducing the hydrolysis of PLs and the release of FFAs. It is reasonable to hypothesize that alterations in PL concentrations are closely related to the pathogenesis of AD, as PLs perform a number of important cellular roles, including stabilization of membrane ion channels, neurotransmission, and the localization of A ␤ plaques to PL cores ( 6, 7 ).As a result of progress in MS, and MALDI-imaging MS (IMS) in particular, the analysis of PL changes during disease progression has become feasible. MALDI-IMS is a unique tool that integrates molecular and histological information together with information attained using Alzheimer's disease (AD), the most common form of dementia, is primarily caused by abnormal protein kinesis and the accumulation of aggregated proteins in the brain. This work was supported

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“…Models describing the effects of circulation on endothelial metabolites have also been built ( 123 ). Endothelial NO interactions ( 124 – 126 ), Ca 2+ signaling ( 127 ) along with protein ( 128 ) and mechanical ( 119 ) signaling have also been addressed with computational modeling. Models have been individualized using patient data and have explored the effects of stenting on blood flow ( 129 – 132 ).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

McGarrity

Halldórsson

Palsson

et al. 2016

Front. Cardiovasc. Med.

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High-throughput biochemical profiling has led to a requirement for advanced data interpretation techniques capable of integrating the analysis of gene, protein, and metabolic profiles to shed light on genotype–phenotype relationships. Herein, we consider the current state of knowledge of endothelial cell (EC) metabolism and its connections to cardiovascular disease (CVD) and explore the use of genome-scale metabolic models (GEMs) for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate CVD-related genetic variation, drug resistance mechanisms, and novel metabolic pathways in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for CVDs based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health and disease, are thus highlighted.

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An Integrated Mathematical Model of Thrombin-, Histamine-and VEGF-Mediated Signalling in Endothelial Permeability

Cited by 17 publications

References 101 publications

Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation

Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation

Global changes of phospholipids identified by MALDI imaging mass spectrometry in a mouse model of Alzheimer's disease

Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

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