Dellsperger KC. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 294: H2659-H2668, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00953.2007.-The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22 phox , and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P Ͻ 0.05). Tempol decreased RVSP (P Ͻ 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22 phox , and Rac-1 protein expression, and ROS in Ren2 rats (P Ͻ 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P Ͻ 0.001) and luminal surface area was 54% less (P Ͻ 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P Ͻ 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling. renin; angiotensin II; NADPH oxidase CARDIOVASCULAR GENERATION of reactive oxygen species (ROS), such as superoxide and H 2 O 2 , has been implicated in the pathogenesis of hypertension, cardiac hypertrophy, pulmonary hypertension (PH), and heart failure (7). Molecular complexes known to generate superoxide within vascular endothelial and smooth muscle cells (SMC) include the NADPH oxidases (18), xanthine oxidase (32), the mitochondrial transport chain, and uncoupled nitric oxide synthase (NOS) (10,19). NADPH oxidase is a major source of ROS in the vasculature and is activated by hormones, growth factors, cytokines, and shear stress (16). An important stimulus for NADPH oxidase-generated ROS is ANG II. In fact, many of the deleterious effects of ANG II on vascular structure and function are mediated by ROS generation (16,73). ANG II causes rapid induction of NADPH oxidase-dependent superoxide synthesis via PKC (15) and more prolonged stimulation via transactivation of growth factors (62, 69). ANG II also causes redox-sensitive xanthine oxidase activation and endothelial N...
W illiams-Beuren syndrome (WBS, OMIM 194050) is a microdeletion syndrome caused by hemizygosity for multiple genes in 7q11.23 including the elastin locus (ELN).1 2 The classical WBS phenotype comprises elastin arteriopathy (supravalvular aortic stenosis and/or peripheral pulmonary stenosis), connective tissue abnormalities (for example, abnormal joint mobility, hernia and diverticula, hoarse voice), and a particular facial appearance (supraorbital fullness, stellate pattern of the iris, short nose with long philtrum, full lips, and wide mouth). Other frequent features are growth and psychomotor retardation with muscular hypotonia, limited visuospatial cognition, and specific language as well as behavioural abnormalities (overfriendliness and anxiety disorders, hypersensitivity to sounds).3-5 Endocrine and metabolic disturbances (infantile hypercalcaemia) may occur.Despite at least 21 genes having been identified in the common 1.5 Mb deletion interval in humans, 6 their individual contribution to the multisystem phenotype of WBS is unclear. So far, only the gene coding for elastin (ELN) has been proven to be causally involved 7 : ELN is deleted in all WBS patients with a microdeletion 7q11.23 who have been reported to date. However, hemizygosity for ELN alone does not cause WBS, but isolated supravalvular aortic stenosis (SVAS).8 Hence, haploinsufficiency for ELN is necessary but not sufficient for WBS.Molecular dissection of the WBS phenotype is hindered by the fact that over 95% of patients with the classical phenotype carry an apparently identical ∼1.5 Mb deletion interval.9-11 This constant size is explained by non allelic-homologous recombination between duplicons flanking the deletion interval.12 The presence of these direct repeats is assumed to be a predisposing factor for the WBS microdeletion that occurs with a frequency of approximately 1 in 20 000 liveborn children. 12So far, several cases of either classical WBS or SVAS with or without cognitive deficits have been found to be associated with a smaller deletion. In seven of these cases an alternative proximal breakpoint was involved, and an eighth case featured an alternative distal breakpoint [13][14][15][16] (reviewed in Osborne 2 ). We present a further independent case with an atypical deletion but with the classical WBS phenotype. Together, these cases indicate that the critical WBS region is smaller than 1.5 Mb. CASE REPORT AND METHODSThe patient and his healthy twin sister were born to non-consanguineous parents (maternal age 26, paternal age 41) after an uneventful pregnancy. Birth weight, height, and head circumference were within the normal range for twins. The constellation of supravalvular aortic stenosis, pulmonary Key points• We present the case of a patient with the classical phenotype of Williams-Beuren syndrome who has only a partial deletion of the common 1.5 Mb deletion interval at 7q11.23.• Fluorescence in situ hybridisation (FISH) with the commercial WBSCR probe (from Appligene/Oncor) showed two specific signals in each metaphas...
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