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Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling.

Silva MA, Bruder-Nascimento T, Cau SB, Lopes RA, Mestriner FL, Fais RS, Touyz RM, Tostes RC - Front Physiol (2015)

Bottom Line: Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2.We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes.Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.

ABSTRACT
Type 2 diabetes (DM2) increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes. Leptin receptor knockout [LepR(db)/LepR(db) (db/db)] mice, a model of DM2, and their counterpart controls [LepR(db)/LepR(+), (db/+) mice] received spironolactone (50 mg/kg body weight/day) or vehicle (ethanol 1%) via oral per gavage for 6 weeks. Spironolactone treatment abolished endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS) phosphorylation (Ser(1177)) in arteries from db/db mice, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 and catalase expression, improved sodium nitroprusside and BAY 41-2272-induced relaxation, and increased soluble guanylyl cyclase (sGC) β subunit expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox-sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes.

No MeSH data available.


Related in: MedlinePlus

Protein expression of sGC α (A), sGC β (B) and p-eNOS (C) protein in mesenteric arteries from db/db and db/+ mice treated with spironolactone or vehicle for 6 weeks. Representative images are displayed in (D). β-actin and total eNOS expression were also determined and used as internal controls. Data are expressed as mean ± SEM. *P < 0.05 vs. respective db/+ group, #P < 0.05 vs. db/db vehicle; V, vehicle; S, spironolactone, n = 5.
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Figure 5: Protein expression of sGC α (A), sGC β (B) and p-eNOS (C) protein in mesenteric arteries from db/db and db/+ mice treated with spironolactone or vehicle for 6 weeks. Representative images are displayed in (D). β-actin and total eNOS expression were also determined and used as internal controls. Data are expressed as mean ± SEM. *P < 0.05 vs. respective db/+ group, #P < 0.05 vs. db/db vehicle; V, vehicle; S, spironolactone, n = 5.

Mentions: To determine whether impaired BAY 41-2272-induced relaxation in arteries from db/db mice was associated with downregulation of sGC, vascular sGC protein content was determined. Figures 5A,B show that mesenteric arteries from db/db and non-diabetic mice present similar expression of sGC α subunit. However, decreased sGC β subunit protein expression was observed in arteries from db/db mice compared to db/+ mice. Spironolactone treatment increased sGC α subunit and restored sGC β subunit expression in arteries from db/db mice.


Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling.

Silva MA, Bruder-Nascimento T, Cau SB, Lopes RA, Mestriner FL, Fais RS, Touyz RM, Tostes RC - Front Physiol (2015)

Protein expression of sGC α (A), sGC β (B) and p-eNOS (C) protein in mesenteric arteries from db/db and db/+ mice treated with spironolactone or vehicle for 6 weeks. Representative images are displayed in (D). β-actin and total eNOS expression were also determined and used as internal controls. Data are expressed as mean ± SEM. *P < 0.05 vs. respective db/+ group, #P < 0.05 vs. db/db vehicle; V, vehicle; S, spironolactone, n = 5.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4593519&req=5

Figure 5: Protein expression of sGC α (A), sGC β (B) and p-eNOS (C) protein in mesenteric arteries from db/db and db/+ mice treated with spironolactone or vehicle for 6 weeks. Representative images are displayed in (D). β-actin and total eNOS expression were also determined and used as internal controls. Data are expressed as mean ± SEM. *P < 0.05 vs. respective db/+ group, #P < 0.05 vs. db/db vehicle; V, vehicle; S, spironolactone, n = 5.
Mentions: To determine whether impaired BAY 41-2272-induced relaxation in arteries from db/db mice was associated with downregulation of sGC, vascular sGC protein content was determined. Figures 5A,B show that mesenteric arteries from db/db and non-diabetic mice present similar expression of sGC α subunit. However, decreased sGC β subunit protein expression was observed in arteries from db/db mice compared to db/+ mice. Spironolactone treatment increased sGC α subunit and restored sGC β subunit expression in arteries from db/db mice.

Bottom Line: Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2.We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes.Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo Ribeirão Preto, Brazil.

ABSTRACT
Type 2 diabetes (DM2) increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes. Leptin receptor knockout [LepR(db)/LepR(db) (db/db)] mice, a model of DM2, and their counterpart controls [LepR(db)/LepR(+), (db/+) mice] received spironolactone (50 mg/kg body weight/day) or vehicle (ethanol 1%) via oral per gavage for 6 weeks. Spironolactone treatment abolished endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS) phosphorylation (Ser(1177)) in arteries from db/db mice, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 and catalase expression, improved sodium nitroprusside and BAY 41-2272-induced relaxation, and increased soluble guanylyl cyclase (sGC) β subunit expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox-sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes.

No MeSH data available.


Related in: MedlinePlus