Inhibition of myeloid differentiation factor-2 attenuates obesity-induced cardiomyopathy and fibrosis
Inhibition of myeloid differentiation factor-2 attenuates obesity-induced cardiomyopathy and fibrosis
复制标题
抑制骨髓分化因子 2 可减轻肥胖引起的心肌病和纤维化
DOI：
10.1016/j.bbadis.2017.09.026
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发表时间：
2018-01-01
影响因子：
6.2
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Fang, Qilu;Wang, Jingying;Wang, Yi
肥胖通过慢性组织炎症引起心血管疾病，包括心脏肥大和重塑。髓样分化因子-2（MD 2）是一种脂多糖结合蛋白，在内毒素诱导的急性炎症性疾病中对促炎通路的激活具有重要的功能。在这里，我们测试了MD 2在肥胖引起的心肌病中起核心作用的假设。用高脂肪饮食（HFD）或正常饮食（对照）喂养野生型或MD 2敲除小鼠总共16周，并从第9周开始施用MD 2抑制剂L 6 H21（20 mg/kg）或媒介物（1% CMC-Na）。HFD诱导显著的体重增加和心脏肥大，心脏纤维化和炎症增加。L 6 H21施用或MD 2敲除减弱HFD诱导的肥胖、炎症和心脏重塑。在体外暴露于高脂诱导H9 C2细胞肥大与激活JNK/ERK和NF-κ B途径，这是取消预处理MD 2抑制剂L 6 H21。我们的研究结果表明，MD 2是必不可少的肥胖相关的心脏肥大，通过激活JNK/ERK和NF-κ B依赖的心脏炎症通路。靶向MD 2将是预防肥胖诱导的心脏损伤和重塑的治疗方法。
Obesity causes cardiovascular diseases, including cardiac hypertrophy and remodeling, via chronic tissue inflammation. Myeloid differentiation factor-2 (MD2), a binding protein of lipopolysaccharide, is functionally essential for the activation of proinflammatory pathways in endotoxin-induced acute inflammatory diseases. Here we tested the hypothesis that MD2 plays a central role in obesity-induced cardiomyopathy. Wildtype or MD2 knockout mice were fed with a high fat diet (HFD) or normal diet (Control) for total 16 weeks, and MD2 inhibitor L6H21 (20 mg/kg) or vehicle (1% CMC-Na) were administered from the beginning of the 9th week. HFD induced significant weight gain and cardiac hypertrophy, with increased cardiac fibrosis and inflammation. L6H21 administration or MD2 knockout attenuated HFD-induced obesity, inflammation and cardiac remodeling. In vitro exposure of H9C2 cells to high lipids induced cell hypertrophy with activated JNK/ERK and NF-kappa B pathways, which was abolished by pretreatment of MD2 inhibitor L6H21. Our results demonstrate that MD2 is essential to obesity-related cardiac hypertrophy through activating JNK/ERK and NF-kappa B-dependent cardiac inflammatory pathways. Targeting MD2 would be a therapeutic approach to prevent obesity-induced cardiac injury and remodeling.