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Abstract 452: Hyperglycemia and Oxidative Stress Impair Fluid Shear Stress-mediated Endothelial Nitric Oxide Synthase Phosphorylation and Activation via Disrupting Adherens Junctions
- Source :
- Arteriosclerosis, Thrombosis, and Vascular Biology. 35
- Publication Year :
- 2015
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2015.
-
Abstract
- Endothelial dysfunction, characterized by a decrease of nitric oxide (NO) bioavailability in the vessel wall, plays a crucial role in the pathogenesis of atherosclerosis. Oxidative stress due to increased reactive oxygen species (ROS) is implicated in endothelial dysfunction associated with diabetes. However the molecular mechanisms by which oxidative stress causes endothelial dysfunction remain incompletely understood. Blood flow, which generates fluid shear stress acting on endothelium, is the most potent physiological stimulus for NO production through endothelial NO synthase (eNOS) activation. Here we report that hyperglycemia and oxidative stress impairs fluid shear stress signal transduction and eNOS activation in endothelium. We found that the exposure of endothelial cells (ECs) to ROS generators such as menadione and xanthine/xanthine oxidase inhibited laminar flow-mediated Akt and eNOS phosphorylation and activation in human endothelial cells. Moreover, ECs pre-exposed to high glucose that generates ROS production in ECs, failed to respond to laminar flow for Akt/eNOS phosphorylation and activation. Consequently NO production from ECs in response to laminar flow was attenuated by high glucose treatment. Mechanistically, we observed that hyperglycemia and oxidative stress altered endothelial adherens junction integrity, manifested by the alternation of the localization of cell-cell junction molecules vascular endothelial cadherin (VE-cadherin) and beta-catenin. Silencing VE-cadherin or beta-catenin with small interference RNA also inhibited laminar flow-mediated signaling for eNOS activation, which mimics the effects of oxidative stress, suggesting that cell-cell junction integrity is critical for fluid shear stress signal transduction and eNOS activation. Collectively, our results demonstrate that hyperglycemia and oxidative stress impair laminar flow-mediated eNOS activation through the alternation of endothelial junction integrity and fluid shear stress signal transduction. Our findings suggest a novel mechanism whereby oxidative stress induces diabetes-associated endothelial dysfunction.
- Subjects :
- medicine.medical_specialty
Endothelium
Biology
medicine.disease
biology.organism_classification
medicine.disease_cause
Cell biology
Nitric oxide
Adherens junction
Nitric oxide synthase
chemistry.chemical_compound
medicine.anatomical_structure
Endocrinology
chemistry
Enos
Internal medicine
medicine
biology.protein
Endothelial dysfunction
Cardiology and Cardiovascular Medicine
Xanthine oxidase
Oxidative stress
Subjects
Details
- ISSN :
- 15244636 and 10795642
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Accession number :
- edsair.doi...........a2f4cec18f5c8bd2fc35d37a87c66751