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 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.