Impaired Glutathione Redox System Paradoxically Suppresses Angiotensin II-Induced Vascular Remodeling

Abstract

BackgroundAngiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown.Methods In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs).ResultsBSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215±4 mmHg by AII at 4 weeks (p<0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52±0.08, 2.50±0.09 and 2.10±0.07 mg/g respectively, p<0.05). Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester.ConclusionsWe demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

Oral Exposure to Atrazine Induces Oxidative Stress and Calcium Homeostasis Disruption in Spleen of Mice

“…Damage to antioxidant capacity can result from overoxidation of GSH (or conversely a reduced ability to regenerate GSH from the GSSG form), as well as an overall reduction in intracellular concentrations of total (GSH + GSSG) glutathione [28]. In the present study, the levels of ROS in splenocytes were elevated; GSH depletion and a decrease in the GSH/GSSG ratio in the serum of the ATR-treated mice were also observed.…”

Metabolism of vascular smooth muscle cells in vascular diseases

“…The GSH depletion is linked to an increase in DNA damage and mediates the exogenous H 2 O 2 -induced growth suppression and cell death of human VSMCs (181,183,197). The oxidative stress in impaired GSH redox system attenuated vascular remodeling through the enhancement of apoptosis and suppression of cell growth (106).…”

Reactive Oxygen Species Generation and Atherosclerosis

“…Elevated levels of glutathione caused reductive stress that contributed to S-glutathionylation and inactivation of SHP-2 (tyrosineprotein phosphatase nonreceptor type 11) phosphatase, what then inhibited ROS1 inactivation 81 ( Figure 3). Interestingly, Izawa et al 82 reported that buthionine sulfoximine, which is glutathione inhibitor, elevated vessel wall superoxide levels, but on the other hand decreased angiotensin II-induced vessel remodeling.…”