MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance
MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance
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DOI：
10.1128/mcb.02186-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Oh, Hidemasa
中科院分区：
文献类型：
--
作者：
Ogata, Takehiro;Ueyama, Tomomi;Oh, Hidemasa
我们发现了一种新的肌肉限制性假定卷曲螺旋蛋白，MURC，这是进化保守的从青蛙到人类。MURC定位于细胞质，并在成年小鼠心脏肌节的Z线中积累。从胚胎期到成年期，心脏中MURC mRNA的表达在发育过程中增加。作为对压力超负荷的反应，肥大心脏中的MURC mRNA表达增加。使用酵母双杂交系统，我们确定了血清剥夺反应（SDPR）蛋白，磷脂酰丝氨酸结合蛋白，作为MURC结合蛋白。MURC诱导RhoA/ROCK通路的激活，该通路调节血清反应因子介导的心房利钠肽（ANP）表达和肌原纤维组织。SDPR增强了心肌细胞中MURC诱导的ANP启动子的反式激活，SDPR的RNA干扰减弱了MURC对ANP启动子的作用。表达心脏特异性MURC（Tg-MURC）的转基因小鼠表现出心脏收缩功能障碍和房室（AV）传导障碍，伴有心房腔扩大、心室壁厚度减少和间质纤维化。在Tg-MURC小鼠中观察到心房颤动和AV阻滞的自发发作。这些发现表明，MURC调节RhoA信号，并且MURC在心功能不全和传导障碍的发展中起重要作用，并增加了对房性心律失常的易感性。
We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.