Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy
- Yong Pan1,2,
- Yi Wang2,
- Yunjie Zhao2,
- Kesong Peng2,
- Weixin Li2,
- Yonggang Wang3,4,
- Jingjing Zhang5,
- Shanshan Zhou3,4,
- Quan Liu3,4,
- Xiaokun Li1,2,
- Lu Cai1,4,* and
- Guang Liang2,*
- 1Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
- 2Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
- 3The First Hospital of Jilin University, 71 Xinmin Street, Changchun, Jilin, China
- 4KCHRI at the Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
- 5Department of Cardiology at the People’s Hospital of Liaoning Province, Shenyang, Liaoning, China
- *Corresponding authors: Guang Liang, E-mail: ; and Lu Cai, E-mail:
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 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 NF-κB in both H9c2 cells and neonatal cardiomyocytes. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to the protection of C66 from inflammation and cell apoptosis, which was validated by the utilization of SP600125 and dn-JNK. The molecular docking and kinase activity assay confirmed C66’s direct binding to and inhibition of JNK. In mice with type 1 diabetes, administration of C66 or SP600125 at 5 mg/kg significantly decreased the plasma and cardiac TNF-α level, accompanied by decreasing cardiac apoptosis, and, finally, improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting the 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.
- Received October 17, 2013.
- Accepted April 28, 2014.
- © 2014 by the American Diabetes Association.
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