Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear.

Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Research Abstract Details 

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Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Abstract Text:

Mandar S Joshi,Chieko Mineo,Philip W Shaul,John Anthony Bauer,

Human endothelial nitric oxide synthase (NOS3) gene polymorphism at Exon 7 (Glu298Asp) has been linked to vascular endothelial dysfunction, but the mechanisms are not defined. Shear is a key modulator of NOS3 function in vivo and association with caveolae is important for the control of NOS3 protein activity. Here we tested the hypothesis that altered enrichment of NOS3 in the caveolar membrane defines Glu298Asp genotype-specific responses and NOS3 activity. Basal caveolar membrane enrichment was carried out to quantitate the NOS3 enrichment in caveolae. Cells were subjected to shear and NOS3 protein levels, phosphorylation, enzyme function were investigated. Variant genotypes had lower NOx production pre- and post-shear, but no genotype-dependent alterations in pNOS3 were observed. Asp variants had significantly lower NOS3 enrichment in the caveolar membrane fraction. Further, immunoprecipitation studies demonstrated that Asp variants had substantially less NOS3/Cav-1 association (approximately 40%) during static conditions. Furthermore, acute shear causes impaired NOS3/Cav-1 dissociation in Asp variants. The results from immunoprecipitation studies were in complete agreement with caveolar membrane preparation findings. Collectively, these data demonstrate functional consequences of the Glu298Asp NOS3 variation and further define disruption of NOS3 caveolar localization and shear-induced mobilization as the primary mechanism responsible for these differences.

Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Publishing Authors By Initials

MS Joshi,C Mineo,PW Shaul,JA Bauer,

For similar genetic phenomena: variation (genetics) research abstracts see: genetic phenomena: variation (genetics) research

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Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The FASEB journal : official publication of the Fe

VOLUME: 21

Page Numbers: 2655-63

Journal Abbreviation: FASEB J.

ISSN: 1530-6860

DAY: 20

MONTH: 04

YEAR: 2007

Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Information

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LANGUAGE: eng

NlmUniqueID: 8804484

Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Keywords Mesh Terms:

KEYWORDS: Variation (Genetics)

MESH TERMS: physiology

Chemical & Substance for Abstract: Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. Information

Substance Name: Nitric Oxide Synthase Type III

Registry Number: EC 1.14.13.39

Grant and Affiliation Information for Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear.

AFFILIATION: Center for Cardiovascular Medicine, Columbus Children's Research Institute, 700 Children's Dr., Columbus, OH 43205, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL63067

ACRONYM: HL

MEDLINETA: FASEB J

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