中心剪接调节因子RBFox2的抑制与压力超负荷诱导的心力衰竭在功能上相关。
Repression of the Central Splicing Regulator RBFox2 Is Functionally Linked to Pressure Overload-Induced Heart Failure.
作者信息
Wei Chaoliang, Qiu Jinsong, Zhou Yu, Xue Yuanchao, Hu Jing, Ouyang Kunfu, Banerjee Indroneal, Zhang Caimei, Chen Biyi, Li Hairi, Chen Ju, Song Long-Sheng, Fu Xiang-Dong
机构信息
Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, CA 92093-0651, USA.
Department of Medicine University of California, San Diego, La Jolla, CA 92093-0651, USA.
出版信息
Cell Rep. 2015 Mar 10;10(9):1521-1533. doi: 10.1016/j.celrep.2015.02.013. Epub 2015 Mar 5.
Heart failure is characterized by the transition from an initial compensatory response to decompensation, which can be partially mimicked by transverse aortic constriction (TAC) in rodent models. Numerous signaling molecules have been shown to be part of the compensatory program, but relatively little is known about the transition to decompensation that leads to heart failure. Here, we show that TAC potently decreases the RBFox2 protein in the mouse heart, and cardiac ablation of this critical splicing regulator generates many phenotypes resembling those associated with decompensation in the failing heart. Global analysis reveals that RBFox2 regulates splicing of many genes implicated in heart function and disease. A subset of these genes undergoes developmental regulation during postnatal heart remodeling, which is reversed in TAC-treated and RBFox2 knockout mice. These findings suggest that RBFox2 may be a critical stress sensor during pressure overload-induced heart failure.
心力衰竭的特征是从最初的代偿反应转变为失代偿，这在啮齿动物模型中可通过横向主动脉缩窄（TAC）部分模拟。许多信号分子已被证明是代偿程序的一部分，但对于导致心力衰竭的失代偿转变过程了解相对较少。在这里，我们表明TAC能显著降低小鼠心脏中的RBFox2蛋白，对这种关键剪接调节因子进行心脏消融会产生许多类似于衰竭心脏中与失代偿相关的表型。全局分析表明，RBFox2调节许多与心脏功能和疾病相关基因的剪接。这些基因中的一部分在出生后心脏重塑过程中受到发育调控，而在TAC处理的小鼠和RBFox2基因敲除小鼠中这种调控被逆转。这些发现表明，RBFox2可能是压力超负荷诱导的心力衰竭过程中的关键应激传感器。
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