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.

Our data indicate that H S is a novel regulator of FoxO1 in cardiac cells and provide evidence supporting the potential of H S in inhibiting the progression of DCM.

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Background. Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation. Methods and Results. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not. Conclusions. Rapamycin may prohibit sestrin1 downregulation through targeting mTORC2 in appeasing LSS induced EC oxidative apoptosis. Our results provide the in vitro evidence to explain the pathophysiology of RES stented arteries.

Recent studies indicate that blockade of currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (particularly HCN1) may partly account for the antinociceptive effects of capsazepine (CPZ). Unfortunately, determining whether capsazepine is a selective HCN channel blocker and determining its adverse effects when it is used for the treatment of neuropathic pain, have been thus far understudied. In this study, we aimed to elucidate the effects of capsazepine on human HCN2 (hHCN2) and HCN4 (hHCN4) channels in HEK293 cells. The vectors that expressed hHCN2 and hHCN4 cDNA were constructed and transfected into HEK293 cells. Enhanced green fluorescent protein (EGFP) fluorescence and the reverse transcription polymerase chain reaction (RT-PCR) were used to confirm the successful transfection of the vectors. After G418 (neomycin) screening, cell lines that expressed hHCN2 and hHCN4 were obtained. The whole-cell voltage-clamp technique was used to determine the currents from hHCN2 and hHCN4 channels, which were perfused with five concentrations (0.1 µM, 1 µM, 5 µM, 10 µM and 50 µM) of capsazepine. The results showed that capsazepine at the range from 0.1 to 50 µM markedly inhibited hHCN2 and hHCN4 currents in a concentration-dependent manner, with most inhibition achieved at a concentration of 10 µM of capsazepine. When compared with the control group, a V0.5 for the hHCN2 and hHCN4 channel showed that 10 µM capsazepine significantly shifted the membrane potential towards hyperpolarization. The present results indicate that capsazepine is not a selective HCN1 channel blocker and that it may have adverse effects when used to treat neuropathic pain.