Inhibition of JNK and p38 MAPK‐mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin‐induced diabetic cardiomyopathy

Inflammation plays a critical role in the development of diabetic cardiomyopathy (DCM), which has been identified as a major predisposing factor for heart failure in diabetic patients. Previous studies indicated that ivabradine (a specific agent for heart rate [HR] reduction) has anti‐inflammatory properties, but its role in DCM remains unknown. This study investigated whether ivabradine exerts a therapeutic effect in DCM. C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ) to induce diabetes; then administered with ivabradine or saline (control). After 12 weeks, the surviving mice were analyzed to determine the cardioprotective effect of ivabradine against DCM. Although treatment with ivabradine did not affect blood glucose levels, it attenuated tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6 messenger RNA (mRNA) expression, inhibited c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase (p38 MAPK) activation, reduced histological abnormalities, myocardial apoptosis and collagen deposition, and improved cardiac function in the diabetic mice. Interestingly, the anti‐inflammatory and antiapoptotic properties of ivabradine, but not its inhibitory effect on JNK and p38 MAPK, were observed in high‐glucose‐cultured neonatal rat ventricular cardiomyocytes. Attenuating inflammation and apoptosis via intramyocardial injection of lentiviruses carrying short hairpin RNA targeting JNK and p38 MAPK validated that the anti‐inflammatory and antiapoptotic effects of ivabradine were partly attributed to JNK and p38 MAPK inactivation in diabetic mice. In summary, these data indicate that ivabradine‐mediated improvement of cardiac function in STZ‐induced diabetic mice may be partly attributed to inhibition of JNK/p38 MAPK‐mediated inflammation and apoptosis, which is dependent on the reduction in HR. (a) The JNK and p38 MAPK protein levels in heart tissues after intramyocardial injection of lentiviruses carrying shRNA targeting JNK (LV‐JNK shRNA) and p38 MAPK (LV‐p38 MAPK shRNA). (b,c) Proinflammatory cytokine mRNA and protein expression were significantly decreased in diabetic mice treated with LV‐JNK shRNA and LV‐p38 MAPK shRNA. Column figure shows the difference in mRNA and protein expression. (d) TUNEL staining of heart tissues in each group.