Gustafson-Wagner Elisabeth A, Sinn Haley W, Chen Yen-Lin, Wang Da-Zhi, Reiter Rebecca S, Lin Jenny L-C, Yang Baoli, Williamson Roger A, Chen Ju, Lin Cheng-I, Lin Jim J-C
Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H2680-92. doi: 10.1152/ajpheart.00806.2007. Epub 2007 Aug 31.
The intercalated disk protein Xin was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXinalpha and mXinbeta. The human homolog of mXinalpha, Cmya1, maps to chromosomal region 3p21.2-21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here we report that mXinalpha-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXinbeta likely provides partial compensation and accounts for the viability of the mXinalpha-null mice. Ultrastructural studies of mXinalpha-null mouse hearts reveal intercalated disk disruption and myofilament disarray. In mXinalpha-null mice, there is a significant decrease in the expression level of p120-catenin, beta-catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated disks and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 are observed in the mXinalpha-null mouse heart, which, together with previously observed abnormal electrophysiological properties of mXinalpha-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on isolated, perfused hearts (Langendorff preparations) show a significantly prolonged QT interval in mXinalpha-deficient hearts. Thus mXinalpha functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disk in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXinalpha-knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.
闰盘蛋白Xin最初是在鸡的横纹肌中发现的，与心脏形态发生有关。在小鼠中，有两个同源基因，即mXinalpha和mXinbeta。mXinalpha的人类同源物Cmya1定位于染色体区域3p21.2 - 21.3，靠近一个伴有传导缺陷的扩张型心肌病2位点。在此我们报告，mXinalpha基因敲除小鼠的心脏肥大并出现纤维化，这是心肌病的表现。mXinbeta的显著上调可能提供了部分补偿，并解释了mXinalpha基因敲除小鼠的存活能力。对mXinalpha基因敲除小鼠心脏的超微结构研究显示闰盘破坏和肌丝紊乱。在mXinalpha基因敲除小鼠中，p120连环蛋白、β-连环蛋白、N-钙黏蛋白和桥粒斑蛋白的表达水平显著降低，这可能会损害闰盘的完整性并在功能上削弱黏附力，导致心脏缺陷。此外，在mXinalpha基因敲除小鼠的心脏中观察到连接蛋白43的定位改变和表达减少，这与之前观察到的mXinalpha缺陷型小鼠心室肌细胞的异常电生理特性一起，可能会导致传导缺陷。事实上，对离体灌注心脏（Langendorff标本）的心电图记录显示，mXinalpha缺陷型心脏的QT间期显著延长。因此，mXinalpha在正常小鼠中可能通过与黏附连接成分和肌动蛋白细胞骨架的关联，发挥调节肥大反应和维持闰盘结构完整性的作用。mXinalpha基因敲除小鼠品系提供了一种伴有传导缺陷的心脏肥大和心肌病的新型模型。
