A novel truncated form of eNOS associates with altered vascular function.
Cardiovasc Res
; 101(3): 492-502, 2014 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-24302629
ABSTRACT
AIMS:
Nitric oxide (NO) plays a key role in vascular homeostasis and is produced by endothelial NO synthase (eNOS), encoded by NOS3 gene. We previously reported the genetic association between NOS3 rs753482-A>C polymorphism on intron 19 and coronary artery disease (CAD). In the attempt of conferring functional implication to the rs753482-A>C polymorphism, we investigated its influence on transcript maturation. METHODS ANDRESULTS:
A transcript variant skipping exons 20-21 is prevalent in carriers of the rs753482-C allele and is translated in a novel truncated form of eNOS. The truncated eNOS displays increased basal NO production, is insensitive to calcium stimulation, and, upon heterodimerization with the full-length eNOS protein, exerts a dominant-negative effect on NO production. CAD patients and healthy subjects' carriers of the rs753482-C genotype are characterized by increased NO basal levels in peripheral blood and platelets, and negatively respond to oral glucose load by failing to increase NO synthesis following insulin wave. Furthermore, forearm vasodilation after reactive hyperaemia is dramatically impaired in rs753482-C carriers.CONCLUSIONS:
We demonstrated that subjects carrying the rs753482-C genotype express a novel stable truncated form of eNOS with altered enzymatic activity that influences NO production and endothelial function. These findings open to new intriguing perspectives to several diseases involving vascular response to NO.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Polimorfismo Genético
/
Doença da Artéria Coronariana
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Endotélio Vascular
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Óxido Nítrico Sintase Tipo III
/
Frequência do Gene
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Aged
/
Humans
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Middle aged
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Itália