Mechanisms underlying the chronic pioglitazone treatment-induced improvement in the impaired endothelium-dependent relaxation seen in aortas from diabetic rats

The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some...

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Bibliographic Details
Published in:Free radical biology & medicine 2007-04, Vol.42 (7), p.993-1007
Main Authors: Matsumoto, Takayuki, Noguchi, Eri, Kobayashi, Tsuneo, Kamata, Katsuo
Format: Article
Language:English
Subjects:
Animals
Aorta
Aorta - drug effects
Aorta - physiopathology
Diabetes
Diabetes Mellitus, Experimental - enzymology
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - physiopathology
Endothelial dysfunction
Endothelin
Endothelin-1 - metabolism
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Endothelium, Vascular - metabolism
Endothelium, Vascular - physiopathology
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - pharmacology
Immunohistochemistry
Male
NADPH Oxidases - metabolism
Nitric oxide
Nitric Oxide - metabolism
Oxidative stress
Pioglitazone
Rats
Rats, Wistar
Superoxide Dismutase - metabolism
Thiazolidinediones - administration & dosage
Thiazolidinediones - pharmacology
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Summary:The objectives of this study were to determine the effects of chronic treatment with pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on the impaired endothelium-dependent relaxation seen in aortas from established streptozotocin (STZ)-induced diabetic rats, and to identify some of the molecular mechanisms involved. Starting at 8 weeks of diabetes, pioglitazone (10 mg/kg) was administered to STZ-induced diabetic rats for 4 weeks. In untreated STZ rats (vs age-matched control rats): (1) ACh-induced relaxation, cGMP accumulation, phosphorylation of the cGMP-dependent protein kinase substrate vasodilator-stimulated phosphoprotein at Ser-239 [an established biochemical end-point of nitric oxide (NO)/cGMP signaling], and Cu/Zn-superoxide dismutase (SOD) expression and SOD activity were all reduced; (2) aortic superoxide generation, nitrotyrosine expression, and NAD(P)H oxidase activity were increased; (3) plasma endothelin-1 (ET-1) and aortic c-Jun (AP-1 component) protein expressions were increased. Pioglitazone treatment markedly corrected the above abnormalities. Collectively, these results suggest that pioglitazone treatment improves endothelium-dependent relaxation by reducing oxidative stress via increased SOD activity, decreased NAD(P)H oxidase activity, and a decreased ET-1 level, and that this decreased ET-1 level may be attributable to an inhibition of the AP-1 signaling pathway.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2006.12.028