Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy.

Abstract

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.

• Authors: Yong Pan, Yi Wang, Yunjie Zhao, Kesong Peng, Weixin Li, Yonggang Wang, Jingjing Zhang, Shanshan Zhou, Quan Liu, Xiaokun Li, Lu Cai, Guang Liang
• Journal: Diabetes (Diabetes) Vol. 63 Issue 10 Pg. 3497-511 (Oct 2014) ISSN: 1939-327X [Electronic] United States
• PMID: 24848068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• NF-kappa B
• JNK Mitogen-Activated Protein Kinases
• Curcumin
• Glucose

Topics

• Animals
• Apoptosis (drug effects)
• Curcumin (analogs & derivatives, pharmacology, therapeutic use)
• Diabetic Cardiomyopathies (chemically induced, drug therapy, prevention & control)
• Glucose
• Inflammation (chemically induced, drug therapy, prevention & control)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, pathology)
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)