Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy.
Hyperglycemia-induced inflammation and apoptosis have important roles in the pathogenesis of diabetic cardiomyopathy. We recently found that a novel curcumin derivative, C66, is able to reduce the high glucose (HG)-induced inflammatory response. This study was designed to investigate the protective effects on diabetic cardiomyopathy and its underlying mechanisms. Pretreatment with C66 significantly reduced HG-induced overexpression of inflammatory cytokines via inactivation of nuclear factor-κB in both H9c2 cells and neonatal cardiomyocytes. Furthermore, we showed that the inhibition of Jun NH2-terminal kinase (JNK) phosphorylation contributed to the protection of C66 from inflammation and cell apoptosis, which was validated by the use of SP600125 and dominant-negative JNK. The molecular docking and kinase activity assay confirmed direct binding of C66 to and inhibition of JNK. In mice with type 1 diabetes, the administration of C66 or SP600125 at 5 mg/kg significantly decreased the levels of plasma and cardiac tumor necrosis factor-α, accompanied by decreasing cardiac apoptosis, and, finally, improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. Thus, this work demonstrated the therapeutic potential of the JNK-targeting compound C66 for the treatment of diabetic cardiomyopathy. Importantly, we indicated a critical role of JNK in diabetic heart injury, and suggested that JNK inhibition may be a feasible strategy for treating diabetic cardiomyopathy.
Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Yong
Y
Pan
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Yi
Y
Wang
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Yunjie
Y
Zhao
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Kesong
K
Peng
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Weixin
W
Li
The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, KY.
Yonggang
Y
Wang
Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang, Liaoning, People's Republic of China.
Jingjing
J
Zhang
The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, KY.
Shanshan
S
Zhou
The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, KY.
Quan
Q
Liu
Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
Xiaokun
X
Li
Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville, Louisville, KY wzmcliangguang@163.com l0cai001@louisville.edu.
Lu
L
Cai
Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China wzmcliangguang@163.com l0cai001@louisville.edu.
Guang
G
Liang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058065:Diabetic Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D005947:Glucose; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D016328:NF-kappa B; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin; D005947:Glucose