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

• 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
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2006.12.028

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.