...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells
【24h】

Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells

机译:人EGF受体2 / EGF受体酪氨酸激酶抑制剂对AMP活化蛋白激酶的激活保护了心脏细胞

获取原文
获取原文并翻译 | 示例
           

摘要

The human EGF receptor (HER) 2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with the anti-HER2 monoclonal antibody trastuzumab (Genentech, South San Francisco, CA), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF receptor tyrosine kinase inhibitor), but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFα-induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro and in the myocardium of GW2974-treated rodents. Calcium chelation or siRNA-targeted AMPK knockdown blocks GW2974 induced fatty acid oxidation. In addition, inhibition of AMPK by a specific inhibitor resulted in increased killing of cardiomyocytes. Elucidating the effects of HER2-targeted therapies on AMPK may predict for risk of cardiomyopathy and provide a novel HER2-targeted strategy designed to protect myocardium from the pro-apoptotic effects of pro-inflammatory cytokines released in response to cardiac injury by chemotherapy or acute ischemia.
机译:人EGF受体(HER)2酪氨酸激酶是人心肌细胞的生存因子,其抑制作用可以解释与抗HER2单克隆抗体曲妥珠单抗(Genentech,South San Francisco,CA)相关的心肌病发生率增加的情况,特别是在曾接受过心脏毒性化学疗法(如蒽环类药物)的患者。在这里,我们显示GW2974(HER2 / EGF受体酪氨酸激酶抑制剂)而非曲妥珠单抗可激活AMP激活的蛋白激酶(AMPK),从而在人心肌细胞中启动代谢应激反应,从而防止TNFα诱导的细胞死亡。 GW2974在体外和在GW2974处理的啮齿动物的心肌中刺激钙依赖性脂肪酸的氧化。钙螯合或靶向siRNA的AMPK敲低可阻断GW2974诱导的脂肪酸氧化。另外,特异性抑制剂对AMPK的抑制导致心肌细胞的杀伤增加。阐明针对AMP2的HER2靶向疗法的效果可能预测了心肌病的风险,并提供了一种新型的针对HER2靶向的策略,旨在保护心肌细胞免受因化学疗法或急性缺血引起的心脏损伤而释放的促炎性细胞因子的促凋亡作用。 。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号