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Inhibition of NOX1 Mitigates Blood Pressure Increases in Elastin Insufficiency.

ABSTRACT: Elastin (ELN) insufficiency leads to the cardiovascular hallmarks of the contiguous gene deletion disorder, Williams-Beuren syndrome, including hypertension and vascular stiffness. Previous studies showed that Williams-Beuren syndrome deletions, which extended to include the NCF1 gene, were associated with lower blood pressure (BP) and reduced vascular stiffness. NCF1 encodes for p47phox, the regulatory component of the NOX1 NADPH oxidase complex that generates reactive oxygen species (ROS) in the vascular wall. Dihydroethidium and 8-hydroxyguanosine staining of mouse aortas confirmed that Eln heterozygotes (Eln^+/- ) had greater ROS levels than the wild-types (Eln^+/+ ), a finding that was negated in vessels cultured without hemodynamic stressors. To analyze the Nox effect on ELN insufficiency, we used both genetic and chemical manipulations. Both Ncf1 haploinsufficiency (Ncf1^+/- ) and Nox1 insufficiency (Nox1^-/y ) decreased oxidative stress and systolic BP in Eln^+/- without modifying vascular structure. Chronic treatment with apocynin, a p47phox inhibitor, lowered systolic BP in Eln^+/- , but had no impact on Eln^+/+ controls. In vivo dosing with phenylephrine (PE) produced an augmented BP response in Eln^+/- relative to Eln^+/+ , and genetic modifications or drug-based interventions that lower Nox1 expression reduced the hypercontractile response to PE in Eln^+/- mice to Eln^+/+ levels. These results indicate that the mechanical and structural differences caused by ELN insufficiency leading to oscillatory flow can perpetuate oxidative stress conditions, which are linked to hypertension, and that by lowering the Nox1-mediated capacity for vascular ROS production, BP differences can be normalized.

SUBMITTER: Troia A

PROVIDER: S-EPMC8248879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: The relationship between hypertension and kidney disease is complicated. Clinical trials found intense blood pressure control was not associated with alterations in glomerular filtration rate (GFR) in all patients but did slow the rate of GFR decline among those with a higher baseline proteinuria. However, the underlying mechanism has been unclear. METHODS: We tested the hypothesis that the association between high blood pressure and renal function is modified by albuminuria status by conducting analyses in a cross-sectional study with 12,440 adult participants without known kidney diseases, diabetes or cardiovascular diseases, participating in the National Health and Nutrition Examination Survey (NHANES) 1999-2006. RESULTS: 1226 out of 12440 were found to have unknown high blood pressure and 4494 were found to have reduced renal function. Overall, a moderate association was found between high blood pressure and renal function insufficiency in all participants analyzed. However, among participants with albuminuria, the prevalence of moderate-severe renal insufficiency substantially and progressively increased from normal subjects to prehypertensive and undiagnosed hypertensive subjects (1.43%, 3.44%, 10.96%, respectively, P for trend<0.0001); on the other hand, the prevalence of undiagnosed hypertension was also significantly higher among subjects with moderate-severe renal insufficiency than those with mild renal insufficiency (35.54% Vs 19.09%, P value <0.05), supporting an association between hypertension and renal function damage. In contrast, no association between hypertension and renal insufficiency was observed among those without albuminuria in this population. Similar findings were observed when the CKD-EPI equation was used. CONCLUSIONS: The association between high blood pressure and reduced renal function could be dependent upon the albuminuria status. This finding may provide a possible explanation for results observed in clinical trials of intensive blood pressure control. Further studies are warranted to confirm our findings.

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Inhibition of NOX1 Mitigates Blood Pressure Increases in Elastin Insufficiency.

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