Abstract
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.
Highlights
Williams-Beuren syndrome (WBS [MIM 194050]) is a developmental disorder with multisystemic manifestations and a prevalence of,1/10,000 newborns, caused by a segmental aneusomy of 1.55–1.83 Mb at chromosomal band 7q11.23, which includes ELN and 25–27 additional genes [1,2]
We have previously shown that a fraction of Williams-Beuren Syndrome (WBS) patients who lack a copy of the NCF1 gene, which codes for p47phox, a subunit of NADPHoxidase (NOX), have lower cardiovascular risk associated with decreased oxidative stress
Cardiovascular phenotype of DD mice related to elevated angiotensin II (angII) and oxidative stress Previously reported mice bearing a heterozygous deletion of half of the orthologous region of the WBS locus (0.67 Mb, from Limk1 to Trim50, including Eln), called DD, were used as a model for the WBS cardiovascular phenotype [11,17]
Summary
Williams-Beuren syndrome (WBS [MIM 194050]) is a developmental disorder with multisystemic manifestations and a prevalence of ,1/10,000 newborns, caused by a segmental aneusomy of 1.55–1.83 Mb at chromosomal band 7q11.23, which includes ELN (coding for elastin [MIM 130160]) and 25–27 additional genes [1,2]. Histological characterization of arterial vessel walls of WBS patients showed increased number and disorganized lamellar structures, fragmented elastic fibers, and hypertrophy of smooth muscle cells [5]. This large arterial vessel remodeling which is a consequence of abnormalities in vascular development, is thought to be responsible for the cardiovascular disease manifested in 84% of WBS patients [4,6]. The arteriopathy is the main cause of serious morbidity in WBS, including systemic hypertension and possible complications such as stroke, cardiac ischemia, and sudden death [8,9]
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