Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes

作者：Wang, Yong yi; Liu, Sha; Lian, Feng; Yang, Wen gang; Xue, Song^*

来源：Acta Pharmacologica Sinica, 2011, 32(5): 565-572.

DOI：10.1038/aps.2011.6

• toll like receptor
• resiquimod
• late preconditioning
• anoxia-reoxygenation
• reactive oxygen species
• cardioprotection

Aim: To investigate whether R-848 (resiquimod, toll-like receptor 7/8 agonist) can induce late preconditioning in neonatal cardiac myocytes.
Methods: The protective effects of R-848 on neonatal myocytes against anoxia-reoxygenation-induced injury were tested, and intracellular reactive oxygen species (ROS) were determined. The protein synthesis inhibitor cyclohexamide (CH) and the ROS scavenger N-acetylcysteine (NAC) were used in this model to test if new protein synthesis and oxidative stress were necessary for their cardioprotective effects. The activation of nuclear factor kappa B (NF kappa B) and hypoxia inducible factor 1 (HIF1) was investigated by electrophoretic mobility shift assays (EMSA), and inducible nitric oxide synthase (iNOS) was assessed by immunoblotting. After iNOS was down-regulated by small interfering RNA (siRNA) transfection, the cardioprotective effect was reassessed.
Results: ROS were triggered soon after R-848 (0.01-1.0 mu g/L) administration, however, the cardioprotective effect of which was induced 24 h later. This protection was abolished by CH or NAC pretreatment. NF kappa B and HIF1 activation and iNOS up-regulation were involved in this protective mechanism. The cardioprotective effect was also attenuated after iNOS was knocked down.
Conclusion: R-848 provided a cardioprotective effect through a late preconditioning mechanism via a ROS/NF kappa B-HIF1/iNOS-dependent pathway.

• 出版日期2011-5
• 单位上海交通大学