Inhibition of JNK by compound C66 prevents pathological changes of the aorta in STZ-induced diabetes.
Cardiovascular diseases as leading causes of the mortality world-wide are related to diabetes. The present study was to explore the protective effect of curcumin analogue C66 on diabetes-induced pathogenic changes of aortas. Diabetes was induced in male C57BL/6 mice with a single intraperitoneal injection of streptozotocin. Diabetic mice and age-matched non-diabetic mice were randomly treated with either vehicle (Control and Diabetes), C66 (C66 and Diabetes/C66) or c-Jun N-terminal kinase (JNK) inhibitor (sp600125, JNKi and Diabetes/JNKi). All three treatments were given by gavage at 5 mg/kg every other day for 3 months. Aortic inflammation, oxidative stress, fibrosis, cell apoptosis and proliferation, Nrf2 expression and transcription were assessed by immunohistochemical staining for the protein level and real-time PCR method for mRNA level. Diabetes increased aortic wall thickness and structural derangement as well as JNK phosphorylation, all of which were attenuated by C66 treatment as JNKi did. 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.
Kosair Children Hospital Research Institute at the Department of Pediatrics of the University of Louisville, Louisville, KY, USA.
Yucheng
Y
Liu
Yonggang
Y
Wang
Xiao
X
Miao
Shanshan
S
Zhou
Yi
Y
Tan
Guang
G
Liang
Yang
Y
Zheng
Quan
Q
Liu
Jian
J
Sun
Lu
L
Cai
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000873:Anthracenes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin
C66; JNK; Nrf2; diabetes; oxidative stress; vascular damage