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.