An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice
An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice
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心肌细胞肌节内含有 FHL1 的复合物介导小鼠肥大的生物力学应激反应。
DOI：
10.1172/jci34472
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发表时间：
2008-12-01
影响因子：
15.9
通讯作者：
Chen, Ju
中科院分区：
文献类型：
--
作者：
Sheikh, Farah;Raskin, Anna;Chen, Ju
心肌细胞对生物力学应激的反应可以决定肥厚性心脏病的病理生理学，靶向调节这些反应的途径是治疗目标。然而，关于心肌细胞肌节如何感知生物力学应力以抑制细胞内肥大信号或这些通路的功能障碍如何导致疾病，人们知之甚少。在这里，我们发现四个半LIM域1（FHL1）是心肌细胞肌节内复合物的一部分，该复合物感知对心脏肥大重要的生物力学应力诱导的反应。缺乏All的小鼠表现出迟钝的肥大反应和对由横向主动脉缩窄引起的压力超负荷的有益功能反应。还观察到与G alpha q（Gq）信号通路的联系，因为Fhl1缺陷可预防Gq转基因小鼠中观察到的心肌病。机制研究表明，FHL1通过肌联蛋白的N2B拉伸传感器结构域感知生物力学应激反应，并启动肌联蛋白和MAPK介导的反应的变化，对肌节伸展性和细胞内信号传导至关重要，从而在病理性肥大的机制中发挥重要作用。这些研究揭示了肌节对肥大应激的生理调节。
The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that fourand-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress-induced responses important for cardiac hypertrophy. Mice lacking All displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the G alpha q (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin- and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.