scholarly journals NFKB1 promoter variation implicates shear-induced NOS3 gene expression and endothelial function in prehypertensives and stage I hypertensives

2007 ◽  
Vol 293 (4) ◽  
pp. H2320-H2327 ◽  
Author(s):  
Joon-Young Park ◽  
Iain K. G. Farrance ◽  
Nicola M. Fenty ◽  
James M. Hagberg ◽  
Stephen M. Roth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Function ◽  
Intracellular Signaling ◽  
Vascular Function ◽  
Stage I ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Nos3 Gene

In endothelial cells, NF-κB is an important intracellular signaling molecule by which changes in wall shear stress are transduced into the nucleus to initiate downstream endothelial nitric oxide synthase ( NOS3) gene expression. We investigated whether NF-κ light-chain gene enhancer in B cells 1 (NFKB1) promoter polymorphism (−94 NFKB1 I/D, where I is the insertion allele and D is the deletion allele) was associated with 1) NOS3 gene expression in endothelial cells under physiological levels of unidirectional laminar shear stress (LSS) and 2) endothelial function in prehypertensive and stage I hypertensive individuals before and after a 6-mo supervised endurance exercise intervention. Competitive EMSAs revealed that proteins present in the nuclei of endothelial cells preferentially bound to the I allele NFKB1 promoter compared with the D allele. Reporter gene assays showed that the I allele promoter had significantly higher activity than the D allele. In agreement with these observations, homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Cells with the homozygous II genotype showed a greater increase in NOS3 protein expression than did homozygous DD genotype cells under LSS. Functional experiments on volunteers confirmed higher baseline reactive hyperemic forearm blood flow, and, furthermore, the subgroup analysis revealed that DD homozygotes were significantly less prevalent in the exercise responder group compared with II and ID genotypes. We conclude that the −94 NFKB1 I/D promoter variation contributes to the modulation of vascular function and adaptability to exercise-induced flow shear stress, most likely due to differences in NFKB1 gene transactivity.

scholarly journals Toxoplasma gondii Dysregulates Barrier Function and Mechanotransduction Signaling in Human Endothelial Cells

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Armond L. Franklin-Murray ◽  
Sharmila Mallya ◽  
Allen Jankeel ◽  
Suhas Sureshchandra ◽  
Ilhem Messaoudi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Toxoplasma Gondii ◽  
Molecular Interactions ◽  
Barrier Function ◽  
Hippo Signaling ◽  
Vascular Endothelial ◽  
Human Endothelial Cells ◽  
Content Type

ABSTRACT Toxoplasma gondii can infect and replicate in vascular endothelial cells prior to entering host tissues. However, little is known about the molecular interactions at the parasite-endothelial cell interface. We demonstrate that T. gondii infection of primary human umbilical vein endothelial cells (HUVEC) altered cell morphology and dysregulated barrier function, increasing permeability to low-molecular-weight polymers. T. gondii disrupted vascular endothelial cadherin (VE-cadherin) and β-catenin localization to the cell periphery and reduced VE-cadherin protein expression. Notably, T. gondii infection led to reorganization of the host cytoskeleton by reducing filamentous actin (F-actin) stress fiber abundance under static and microfluidic shear stress conditions and by reducing planar cell polarity. RNA sequencing (RNA-Seq) comparing genome-wide transcriptional profiles of infected to uninfected endothelial cells revealed changes in gene expression associated with cell-cell adhesion, extracellular matrix reorganization, and cytokine-mediated signaling. In particular, genes downstream of Hippo signaling and the biomechanical sensor and transcriptional coactivator Yes-associated protein (YAP) were downregulated in infected endothelial cells. Interestingly, T. gondii infection activated Hippo signaling by increasing phosphorylation of LATS1, leading to cytoplasmic retention of YAP, and reducing YAP target gene expression. These findings suggest that T. gondii infection triggers Hippo signaling and YAP nuclear export, leading to an altered transcriptional profile of infected endothelial cells. IMPORTANCE Toxoplasma gondii is a foodborne parasite that infects virtually all warm-blooded animals and can cause severe disease in individuals with compromised or weakened immune systems. During dissemination in its infected hosts, T. gondii breaches endothelial barriers to enter tissues and establish the chronic infections underlying the most severe manifestations of toxoplasmosis. The research presented here examines how T. gondii infection of primary human endothelial cells induces changes in cell morphology, barrier function, gene expression, and mechanotransduction signaling under static conditions and under the physiological conditions of shear stress found in the bloodstream. Understanding the molecular interactions occurring at the interface between endothelial cells and T. gondii may provide insights into processes linked to parasite dissemination and pathogenesis.

Myosin Light Chain Gene Expression Associated with Disease States of the Human Heart

1993 ◽  
Vol 25 (5) ◽  
pp. 577-585 ◽  
Author(s):  
T. Trahair ◽  
T. Yeoh ◽  
T. Cartmill ◽  
A. Keogh ◽  
P. Spratt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Light Chain ◽  
Human Heart ◽  
Myosin Light Chain ◽  
Chain Gene ◽  
Light Chain Gene ◽  
Disease States

scholarly journals Deep transcriptomic profiling reveals the similarity between endothelial cells cultured under static and oscillatory shear stress conditions

2016 ◽  
Vol 48 (9) ◽  
pp. 660-666 ◽  
Author(s):  
Congzhen Qiao ◽  
Fan Meng ◽  
Inhwan Jang ◽  
Hanjoong Jo ◽  
Y. Eugene Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Function ◽  
Stress Conditions ◽  
Individual Gene ◽  
Gene Level ◽  
The Individual ◽  
Oscillatory Shear Stress ◽  
Whole Transcriptome ◽  
Transcriptome Level

Atherosclerosis is a multifactorial disease that preferentially develops in specific regions in the arterial tree. This characteristic is mainly attributed to the unique pattern of hemodynamic shear stress in vivo. High laminar shear stress (LS) found in straight lumen exerts athero-protective effects. Low or oscillatory shear stress (OS) present in regions of lesser curvature and arterial bifurcations predisposes arterial intima to atherosclerosis. Shear stress-regulated endothelial function plays an important role in the process of atherosclerosis. Most in vitro research studies focusing on the molecular mechanisms of endothelial function are performed in endothelial cells (ECs) under cultured static (ST) condition. Some findings, however, are not recapitulated in subsequent translational studies, mostly likely due to the missing biomechanical milieu. Here, we profiled the whole transcriptome of primary human coronary arterial endothelial cells (HCAECs) under different shear stress conditions with RNA sequencing. Among 16,313 well-expressed genes, we detected 8,177 that were differentially expressed in OS vs. LS conditions and 9,369 in ST vs. LS conditions. Notably, only 1,618 were differentially expressed in OS vs. ST conditions. Hierarchical clustering of ECs demonstrated a strong similarity between ECs under OS and ST conditions at the transcriptome level. Subsequent pairwise heat mapping and principal component analysis gave further weight to the similarity. At the individual gene level, expressional analysis of representative well-known genes as well as novel genes showed a comparable amount at mRNA and protein levels in ECs under ST and OS conditions. In conclusion, the present work compared the whole transcriptome of HCAECs under different shear stress conditions at the transcriptome level as well as at the individual gene level. We found that cultured ECs are significantly different from those under LS conditions. Thus using cells under ST conditions is unlikely to elucidate endothelial physiology. Given the revealed high similarities of the endothelial transcriptome under OS and ST conditions, it may be helpful to understand the underlying mechanisms of OS-induced endothelial dysfunction from static cultured endothelial studies.

Bidirectional Oscillatory Shear Stress Increases Pro-Atherogenic Gene Expressions (I-CAM1, E-Selectin and IL-6) in Endothelial Cells

2011 ◽  
Author(s):  
Amlan Chakraborty ◽  
Venkatakrishna R. Jala ◽  
Sutirtha Chakraborty ◽  
R. Eric Berson ◽  
M. Keith Sharp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Atherosclerotic Plaque ◽  
Inflammatory Diseases ◽  
Leukotriene B4 ◽  
Oscillatory Shear ◽  
Gene Expressions

Wall shear stress (WSS) plays a key role in altering intracellular pathways and gene expression of endothelial cells, and has significant impacts on atherosclerotic plaque development (1–3). Further, the atherogenic regulators Leukotriene B4 (LTB4) and Lipopolysaccharide (LPS) have significant impacts on the pathophysiology of many inflammatory diseases. This study investigates the effects of oscillatory shear directionality on pro-atherogenic gene expression (I-CAM, E-Selectin, and IL-6) in the presence of LTB4 and LPS. An orbital shaker was used to expose the endothelial cells to oscillatory shear in culture dishes, and Computational fluid dynamics (CFD) was applied to quantify the shear stress on the bottom of the orbiting dish. Directionality of oscillatory shear was characterized by a newly developed hemodynamic parameter — Directional oscillatory shear index (DOSI), which was demonstrated in a previous study to significantly impact cell morphology (4). Results showed that DOSI significantly altered gene expression. Therefore, directionality of shear modulates atherosclerotic gene expression in vitro and thus, may influence the formation of atherosclerotic plaque in vivo.

Shear stress and KLF2 suppress basal inflammatory gene expression in endothelial cells by inhibiting ATF-2

2006 ◽  
Vol 45 (3) ◽  
pp. 178-179
Author(s):  
J.O. Fledderus ◽  
J.V. van Thienen ◽  
R.A. Boon ◽  
R.J. Dekker ◽  
A.P.J.J. Bijnens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

Fluid Shear Stress Reduces Simvastatin Induced Adhesion Molecule Expression in Cytokine Activated Endothelial Cells

2009 ◽  
Author(s):  
Joanna Rossi ◽  
Léonie Rouleau ◽  
Jean-Claude Tardif ◽  
Richard L. Leask
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Adhesion Molecule ◽  
Fluid Shear Stress ◽  
Lipid Lowering ◽  
Adhesion Molecule Expression ◽  
Fluid Shear ◽  
Endothelial Cell Function ◽  
Static Conditions

Although originally designed as inhibitors of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are now known to also have non-lipid lowering benefits [1]. Statins have been reported to modulate gene expression in endothelial cells, however, the effect of statins on adhesion molecule expression is contradictory. Some studies report a decrease in adhesion molecule mRNA and/or protein after statin treatment [2], while others have shown that statins potentiate the effect of tumor necrosis factor alpha (TNFα) [3]. To the best of our knowledge, the effects of statins on gene expression in cultured endothelial cells has been done in static conditions only and no study has examined the effect of blood flow. This is particularly important since fluid shear stress is a strong regulator of endothelial cell function and phenotype [4]. The purpose of this study was to clarify the effects of statins on vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells by evaluating their biological response under fluid flow.

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