Inhibition of JNK by compound C66 prevents pathological changes of the aorta in STZ-induced diabetes.
Bottom Line: Inhibition of JNK phosphorylation by C66 and JNKi also significantly prevented diabetes-induced increases in inflammation, oxidative and nitrative stress, apoptosis, cell proliferation and fibrosis.Furthermore, inhibition of JNK phosphorylation by C66 and JNKi significantly increased aortic Nrf2 expression and transcription function (e.g. increased expression of Nrf2-downstream genes) in normal and diabetic conditions.These results suggest that diabetes-induced pathological changes in the aorta can be protected by C66 via inhibition of JNK function, accompanied by the up-regulation of Nrf2 expression and function.
Affiliation: Kosair Children Hospital Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, KY, USA.Show MeSH
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Mentions: As oxidative stress was considered as the pivotal mediator for various cardiovascular complications of diabetic patients, we assume that the above pathological changes in the aortas of DM mice may all be attributed to the increased oxidative stress, and the protective effect by C66 or even JNKi on diabetes-induced aortic pathogenesis may be mediated by up-regulation of endogenous antioxidants; therefore the next study was to examine the expression and transcription of Nrf2. Figure7 showed that diabetes significantly increased the expression of Nrf2 protein (Fig.7A and B) and mRNA (Fig.7C) in the aorta of DM group compared to control. Diabetes also slightly up-regulated the expression of p-Nrf2 protein (Fig.8A and B) and the expression of Nrf2-downstream antioxidant genes: CAT (Fig.8C) and NQO-1 (Fig.8D). Both treatments with C66 and JNKi significantly and even synergistically increased Nrf2 expression (Fig.7) and function (Fig.8) in non-diabetic mice and diabetic mice respectively.
Affiliation: Kosair Children Hospital Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, KY, USA.