TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.
TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.
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DOI：
10.1038/srep37001
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发表时间：
2016-11-11
影响因子：
4.6
通讯作者：
Nishida M
中科院分区：
文献类型：
--
作者：
Kitajima N;Numaga-Tomita T;Watanabe M;Kuroda T;Nishimura A;Miyano K;Yasuda S;Kuwahara K;Sato Y;Ide T;Birnbaumer L;Sumimoto H;Mori Y;Nishida M
由NADPH氧化酶2 （Nox2）产生的活性氧（ROS）在心脏对机械负荷的生理适应和不适应重构过程中都是机械转导的关键介质。尽管心脏Nox2表达水平较低。然而，从适应到不适应的转变机制仍然不清楚。我们证明了瞬时受体电位规范3 (TRPC3)，一个Ca2+可渗透通道，作为心肌细胞中ROS （PRROS）的正调节因子，并特异性调节小鼠压力过载诱导的适应性不良心脏重塑。TRPC3在特定的c端位点与Nox2发生物理相互作用，从而保护Nox2免受蛋白酶体依赖性降解，并通过TRPC3介导的背景Ca2+进入放大Ca2+依赖性Nox2激活。Nox2还能稳定TRPC3蛋白，增强TRPC3通道活性。TRPC3 c端多肽的表达通过破坏TRPC3- nox2相互作用来消除TRPC3调节的ROS产生，而不影响TRPC3介导的Ca2+内流。新的TRPC3作为PRROS的功能为舒张期Ca2+内流如何特异性编码信号诱导ros介导的适应性不良重构提供了机制解释，并提供了新的治疗可能性。
Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities.
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影响因子：
11.4
作者：
Nishida, M;Sugimoto, K;Mori, Y
通讯作者：
Mori, Y
影响因子：
4.8
作者：
Miyano, Kei;Ueno, Noriko;Sumimoto, Hideki
通讯作者：
Sumimoto, Hideki
影响因子：
20.1
作者：
Patel, Vaibhav B.;Wang, Zuocheng;Oudit, Gavin Y.
通讯作者：
Oudit, Gavin Y.
DOI：
10.1073/pnas.0902761106
发表时间：
2009-05-05
影响因子：
11.1
作者：
Ramsey, I. Scott;Ruchti, Evelyne;Clapham, David E.
通讯作者：
Clapham, David E.
影响因子：
56.9
作者：
Prosser, Benjamin L.;Ward, Christopher W.;Lederer, W. J.
通讯作者：
Lederer, W. J.