Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China.
Basic Res Cardiol. 2011 Sep;106(5):787-99. doi: 10.1007/s00395-011-0182-z. Epub 2011 May 1.
Activation of NF-κB contributes to cardiac hypertrophy and the interleukin-1 receptor (IL-1R)-mediated MyD88-dependent signaling pathway predominately activates NF-κB. Recent studies have shown that the TIR/BB-Loop mimetic (AS-1) disrupted the interaction of MyD88 with the IL-1R, resulting in blunting of NF-κB activation. We have examined the effects of AS-1 on the IL-1β-induced hypertrophic response using cultured neonatal cardiac myocytes in vitro and transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy in vivo. Neonatal cardiac myocytes were treated with AS-1 15 min prior to IL-1β stimulation for 24 h. AS-1 treatment significantly attenuated IL-1β-induced hypertrophic responses of cardiac myocytes. In vivo experiments showed that AS-1 administration prevented cardiac hypertrophy and dysfunction induced by pressure overload. AS-1 administration disrupted the interaction of IL-1R with MyD88 in the pressure overloaded hearts and prevented activation of NF-κB. In addition, AS-1 prevented increases in activation of the MAPK pathway (p38 and p-ERK) in TAC-induced hypertrophic hearts. Our data suggest that the IL-1R-mediated MyD88-dependent signaling pathway plays a role in the development of cardiac hypertrophy and AS-1 attenuation of cardiac hypertrophy is mediated by blocking the interaction between IL-1R and MyD88, resulting in decreased NF-κB binding activity and decreased MAPK activation.
NF-κB 的激活有助于心脏肥大，而白细胞介素-1 受体 (IL-1R) 介导的 MyD88 依赖性信号通路主要激活 NF-κB。最近的研究表明，TIR/BB-Loop 模拟物 (AS-1) 破坏了 MyD88 与 IL-1R 的相互作用，导致 NF-κB 激活减弱。我们使用体外培养的新生心肌细胞和体内横主动脉缩窄 (TAC) 压力超负荷诱导的心脏肥大模型，研究了 AS-1 对 IL-1β 诱导的肥大反应的影响。在 IL-1β 刺激前 15 分钟用 AS-1 处理新生心肌细胞 24 小时。AS-1 处理显著减弱了 IL-1β 诱导的心肌细胞肥大反应。体内实验表明，AS-1 给药可预防压力超负荷引起的心脏肥大和功能障碍。AS-1 给药破坏了压力超负荷心脏中 IL-1R 与 MyD88 的相互作用，并阻止了 NF-κB 的激活。此外，AS-1 可防止 TAC 诱导的肥大心脏中 MAPK 通路 (p38 和 p-ERK) 的激活增加。我们的数据表明，IL-1R 介导的 MyD88 依赖性信号通路在心脏肥大的发展中起作用，AS-1 减弱心脏肥大是通过阻断 IL-1R 与 MyD88 之间的相互作用来介导的，从而降低 NF-κB 结合活性和 MAPK 激活。
