Limits...
Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

Izawa K, Okada M, Sumitomo K, Nakagawa N, Aizawa Y, Kawabe J, Kikuchi K, Hasebe N - PLoS ONE (2014)

Bottom Line: BSO reduced whole blood GSH levels.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).The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.

ABSTRACT

Background: Angiotensin 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).

Results: BSO 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.

Conclusions: We 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.

Show MeSH

Related in: MedlinePlus

BSO inhibited AII induced medial thickness of coronary artery.(A) The effects of AII and BSO on coronary arteries. Representative micrographs of cross sections of coronary arteries with hematoxylin and eosin staining. : magnification ×400, Bar indicates 100 µm. (B) Graphs shows coronary wall to lumen ratio. Bar graphs represent mean ± SD (*p<0.01 vs AII+BSO, n = 7 of each).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4208744&req=5

pone-0108115-g003: BSO inhibited AII induced medial thickness of coronary artery.(A) The effects of AII and BSO on coronary arteries. Representative micrographs of cross sections of coronary arteries with hematoxylin and eosin staining. : magnification ×400, Bar indicates 100 µm. (B) Graphs shows coronary wall to lumen ratio. Bar graphs represent mean ± SD (*p<0.01 vs AII+BSO, n = 7 of each).

Mentions: The medial thickness of aortas was not significantly increased by BSO (0.62±0.03 mm) as compared to control (0.60±0.02 mm). However, it was significantly increased by AII (0.83±0.03 mm, p<0.01) and the increase was significantly suppressed by the co-treatment with BSO (0.73±0.03 mm, p<0.05) (Figure 2). The wall to lumen ratio of coronary arteries was not significantly affected by BSO (0.15±0.01), but was significantly increased by AII (0.10±0.02 mm to 0.26±0.03 mm, p<0.01) as well (Figure 3). The increase in the wall to lumen ratio by AII was also suppressed by the co-treatment with BSO (0.15±0.01 mm) (Figure 3).


Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

Izawa K, Okada M, Sumitomo K, Nakagawa N, Aizawa Y, Kawabe J, Kikuchi K, Hasebe N - PLoS ONE (2014)

BSO inhibited AII induced medial thickness of coronary artery.(A) The effects of AII and BSO on coronary arteries. Representative micrographs of cross sections of coronary arteries with hematoxylin and eosin staining. : magnification ×400, Bar indicates 100 µm. (B) Graphs shows coronary wall to lumen ratio. Bar graphs represent mean ± SD (*p<0.01 vs AII+BSO, n = 7 of each).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4208744&req=5

pone-0108115-g003: BSO inhibited AII induced medial thickness of coronary artery.(A) The effects of AII and BSO on coronary arteries. Representative micrographs of cross sections of coronary arteries with hematoxylin and eosin staining. : magnification ×400, Bar indicates 100 µm. (B) Graphs shows coronary wall to lumen ratio. Bar graphs represent mean ± SD (*p<0.01 vs AII+BSO, n = 7 of each).
Mentions: The medial thickness of aortas was not significantly increased by BSO (0.62±0.03 mm) as compared to control (0.60±0.02 mm). However, it was significantly increased by AII (0.83±0.03 mm, p<0.01) and the increase was significantly suppressed by the co-treatment with BSO (0.73±0.03 mm, p<0.05) (Figure 2). The wall to lumen ratio of coronary arteries was not significantly affected by BSO (0.15±0.01), but was significantly increased by AII (0.10±0.02 mm to 0.26±0.03 mm, p<0.01) as well (Figure 3). The increase in the wall to lumen ratio by AII was also suppressed by the co-treatment with BSO (0.15±0.01 mm) (Figure 3).

Bottom Line: BSO reduced whole blood GSH levels.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).The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.

ABSTRACT

Background: Angiotensin 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).

Results: BSO 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.

Conclusions: We 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.

Show MeSH
Related in: MedlinePlus