Reduction of NADPH-oxidase activity ameliorates the cardiovascular phenotype in a mouse model of Williams-Beuren Syndrome

A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a pr...

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Published in:PLoS genetics 2012-02, Vol.8 (2), p.e1002458
Main Authors: Campuzano, Victoria, Segura-Puimedon, Maria, Terrado, Verena, Sánchez-Rodríguez, Carolina, Coustets, Mathilde, Menacho-Márquez, Mauricio, Nevado, Julián, Bustelo, Xosé R, Francke, Uta, Pérez-Jurado, Luis A
Format: Article
Language:English
Subjects:
Acetophenones - pharmacology
Angiotensin II - genetics
Angiotensin II - metabolism
Angiotensin II Type 1 Receptor Blockers - pharmacology
Animals
Arteries - pathology
Biology
Blood pressure
Blood Pressure - drug effects
Blood Pressure - genetics
Blood Pressure - physiology
Cardiomegaly - pathology
Cardiovascular disease
Constriction, Pathologic - pathology
Disease Models, Animal
Elastin - deficiency
Elastin - genetics
Enzyme Activation - drug effects
Enzyme Inhibitors - pharmacology
Experiments
Genes
Genetic aspects
Genetic engineering
Genotype & phenotype
Humans
Hypertension
Hypertension - pathology
Inhibidors enzimàtics
Losartan - pharmacology
Medicine
Mice
NADP (Coenzyme)
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Oxidative Stress
Physiological aspects
Pressió sanguínia
Rodents
Sequence Deletion
Williams syndrome
Williams Syndrome - genetics
Williams Syndrome - metabolism
Williams Syndrome - pathology
Williams Syndrome - physiopathology
Williams, Síndrome de
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Summary:A hallmark feature of Williams-Beuren Syndrome (WBS) is a generalized arteriopathy due to elastin deficiency, presenting as stenoses of medium and large arteries and leading to hypertension and other cardiovascular complications. Deletion of a functional NCF1 gene copy has been shown to protect a proportion of WBS patients against hypertension, likely through reduced NADPH-oxidase (NOX)-mediated oxidative stress. DD mice, carrying a 0.67 Mb heterozygous deletion including the Eln gene, presented with a generalized arteriopathy, hypertension, and cardiac hypertrophy, associated with elevated angiotensin II (angII), oxidative stress parameters, and Ncf1 expression. Genetic (by crossing with Ncf1 mutant) and/or pharmacological (with ang II type 1 receptor blocker, losartan, or NOX inhibitor apocynin) reduction of NOX activity controlled hormonal and biochemical parameters in DD mice, resulting in normalized blood pressure and improved cardiovascular histology. We provide strong evidence for implication of the redox system in the pathophysiology of the cardiovascular disease in a mouse model of WBS. The phenotype of these mice can be ameliorated by either genetic or pharmacological intervention reducing NOX activity, likely through reduced angII-mediated oxidative stress. Therefore, anti-NOX therapy merits evaluation to prevent the potentially serious cardiovascular complications of WBS, as well as in other cardiovascular disorders mediated by similar pathogenic mechanism.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1002458