Attenuation of aortic injury by ursolic acid through RAGE-Nox-NFκB pathway in streptozocin-induced diabetic rats.
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.
Biotechnology Center, Suzhou Health College, China.
Min
M
Xiang
Jianmei
J
Wang
Yaqin
Y
Zhang
Jing
J
Ling
Xiaoyue
X
Xu
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000293:injuries / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D000097245:Ursolic Acid
D019255:NADPH Oxidases; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014315:Triterpenes; D000097245:Ursolic Acid