TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy
TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy
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DOI：
10.1172/jci.insight.93358
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发表时间：
2017-08-03
期刊：
影响因子：
8
通讯作者：
Nishida, Motohiro
中科院分区：
文献类型：
--
作者：
Shimauchi, Tsukasa;Numaga-Tomita, Takuro;Nishida, Motohiro
心肌萎缩是由于血流动力学卸载引起的心肌消耗。多柔比星是一种高效的抗癌药物，但也通过一种很大程度上未知的机制诱导心肌萎缩。在这里，我们证明，抑制瞬时受体电位典型3（TRPC 3）通道废除阿霉素诱导的小鼠心肌萎缩。阿霉素通过缺氧应激介导的NADPH氧化酶2（Nox 2）的上调增加啮齿动物心肌细胞中ROS的产生，Nox 2与TRPC 3形成稳定的复合物。心肌细胞特异性表达TRPC 3 C-末端小肽抑制TRPC 3-Nox 2偶联，并抑制阿霉素诱导的心肌细胞大小减少和左心室（LV）功能障碍，沿着其上调Nox 2和氧化应激，而不降低缺氧应激。自愿运动，一种有效的治疗，以防止阿霉素诱导的心脏毒性，也下调TRPC 3-Nox 2复合物，并促进容量负荷诱导的LV顺应性，在TRPC 3缺陷的心脏证明。这些结果说明了TRPC 3对LV顺应性和灵活性的影响，并关注TRPC 3-Nox 2复合物，提供了预防多柔比星诱导的心肌病的策略。
Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load-induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy.