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KMID : 0043320120350050877
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Archives of Pharmacal Research
2012 Volume.35 No. 5 p.877 ~ p.886
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Attenuation of aortic injury by ursolic acid through RAGE-Nox-NFκB pathway in streptozocin-induced diabetic rats
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Xiang Min
Wang Jianmei
Zhang Yaqin
Ling Jing
Xu Xiaoyue
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Abstract
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Vascular complications are the leading causes of morbidity and mortality in diabetes mellitus (DM). The RAGE (receptor for advanced glycation end products)-NADPH oxidase-NF-κB signal transduction pathway plays an important role in the development of oxidative stress-related vascular complications in DM. Ursolic acid (UA), a pentacyclic triterpenoid derived from plants, has been reported to have multiple pharmacological effects, including a potent antioxidant activity. This study aimed to investigate both the effect of UA on aortic injury in streptozotocin (STZ)-induced diabetic rats and the drug’s mechanism of action. STZ-induced diabetic animals were randomized in one of the following 4 groups: no treatment (diabetic model group), aminoguanidine (AG, 100 mg/kg), high-dose UA (50 mg/kg), and low-dose UA (25 mg/kg). A non-diabetic control group was followed concurrently. After 8 weeks, the diabetic model rats exhibited: severe aortic arch injury, histologically elevated serum glucose, fructosamine, and glycosylated hemoglobin; and accumulation of advanced glycation end products (AGEs) in the arota. In addition, the levels of RAGE protein, transcription factor NF-κB p65, and the p22phox subunit of NADPH oxidase were increased, as were the serum levels of malondialdehyde and tumor necrosis factor-alpha (TNF-α; p < 0.01 vs control), suggesting that the mechanisms of oxidative stress contributed to vascular injury in the diabetic model group. In contrast, rats treated with UA (50 mg/kg) had a markedly less vascular injury and significantly improved biochemical parameters. Oxidative balance was also normalized in the UA-treated rats, and a marked reduction in the levels of RAGE and p22phox paralleled the reduced activation of NF-κB p65 and TNF-α (p < 0.01 and p < 0.05, respectively, vs diabetic model). These findings suggest that UA may suppress oxidative stress, thus blunting activation of the RAGE-NADPH oxidase-NF-κB signal transduction pathway, to ameliorate vascular injury in the STZ-induced DM rats.
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KEYWORD
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NF-κB, Oxidative stress, p22phox, RAGE, Ursolic acid, Vascular complications
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