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Aldosterone increases oxidant stress to inhibit soluble Guanylyl Cyclase activity in vascular smooth muscle cells
Author(s) -
Maron Bradley Allen,
Zhang Yingyi,
Tang ShiowShih,
Loscalzo Joseph,
Leopold Jane A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.758.26
Subject(s) - soluble guanylyl cyclase , reactive oxygen species , peroxynitrite , chemistry , nitrotyrosine , medicine , endocrinology , vascular smooth muscle , nitric oxide , oxidative stress , apocynin , nadph oxidase , biochemistry , nitric oxide synthase , superoxide , biology , enzyme , guanylate cyclase , smooth muscle
Hyperldosteronism (ALDO) is associated with impaired vascular reactivity. We hypothesized that ALDO‐generated reactive oxygen species (ROS) decrease soluble guanylyl cyclase (sGC) function to inhibit vascular smooth muscle cell (SMC) relaxation. To test this hypothesis, bovine aortic SMC were exposed to ALDO (10 −7 mol/L) or vehicle (V) for 24 h and ROS was measured by 2′‐7′‐dichlorofluorescein fluorescence. ALDO increased ROS by 43% (p<0.04) and 3‐nitrotyrosine immunohistochemistry revealed peroxynitrite formation was increased by 48% (p<0.04) compared to V. Apocynin (APO)(30 mol/L), a NADPH oxidase inhibitor, decreased ALDO‐induced ROS by 25% (p<0.04) and peroxynitrite by 75% (p<0.02). sGC was stimulated exogenously by iNOS activation after SMC exposure to cytokines for 24 h. Without influencing total NO 2 − levels, ALDO reduced iNOS‐mediated cGMP formation by 55% (ANCOVA, p<0.05) and decreased the NO 2 − /NO 3 − ratio by 32% (p<0.04); APO restored cGMP levels (ANCOVA, p<0.05) and the NO 2 −/NO 3 − ratio (p<0.01). Similarly, SMC exposure to DETA‐NONOate (DETA)(10 −3 mol/L) for 24 h increased cGMP levels by 86% (p<0.02) compared to V. ALDO decreased DETA‐stimulated cGMP production by 54% (p<0.02), which was restored by 79% after APO treatment (p<0.02). These data suggest that ALDO‐induced ROS may uncouple NO bioactivity by disrupting key NO‐sGC signaling pathways needed for normal SMC vasodilatory function.