Essential roles of an intercalated disc protein, mXinbeta, in postnatal heart growth and survival.

The Xin repeat-containing proteins, mXinα and mXinβ, localize to the intercalated disc (ICD) of mouse heart and are implicated in cardiac development and function. The mXinα directly interacts with β-catenin, p120-catenin and actin filaments. Ablation of mXinα results in adult late-onset cardiac cardiomyopathy with conduction defects. An up-regulation of the mXinβ in mXinα-deficient hearts suggests a partial compensation. The essential roles of mXinβ in cardiac development and ICD maturation were investigated. Ablation of mXinβ led to abnormal heart shape, ventricular septal defects, severe growth retardation and postnatal lethality with no up-regulation of the mXinα. Postnatal up-regulation of mXinβ in wild type hearts, as well as altered apoptosis and proliferation in mXinβ-null hearts suggest that mXinβ is required for postnatal heart remodeling. The mXinβ-null hearts exhibited a mis-organized myocardium as detected by histological and electron microscopic studies, and an impaired diastolic function as suggested by echocardiography and a delay in switching off the slow skeletal troponin I. Loss of mXinβ resulted in the failure of forming mature ICDs and the mis-localization of mXinα and N-cadherin. The mXinβ-null hearts showed up-regulation of active Stat3 (signal transducer and activator of transcription 3) and down-regulations of the activities of Rac1, IGF-1 (insulin-like growth factor 1) receptor, Akt and Erk1/2 (extracellular-signal-regulated kinases 1/2). These findings identify not only an essential role of mXinβ in the ICD maturation but also mechanisms of mXinβ modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.

含 Xin重复序列的蛋白质，mXinα和mXinβ，定位于小鼠心脏的闰盘（ICD），并与心脏发育和功能有关。mXinα与β -连环蛋白、p120 -连环蛋白和肌动蛋白丝直接相互作用。mXinα的缺失会导致成年晚期发作的伴有传导缺陷的心肌病。mXinα缺陷心脏中mXinβ的上调表明存在部分代偿。 研究了mXinβ在心脏发育和闰盘成熟中的重要作用。 mXinβ的缺失导致心脏形状异常、室间隔缺损、严重的生长迟缓以及出生后致死，且mXinα没有上调。野生型心脏中mXinβ在出生后的上调，以及mXinβ缺失心脏中细胞凋亡和增殖的改变表明mXinβ是出生后心脏重塑所必需的。通过组织学和电子显微镜研究发现，mXinβ缺失的心脏心肌组织紊乱，超声心动图显示舒张功能受损，慢骨骼肌肌钙蛋白I关闭延迟。mXinβ的缺失导致成熟闰盘无法形成，mXinα和N -钙黏蛋白定位错误。mXinβ缺失的心脏中活性Stat3（信号转导和转录激活因子3）上调，Rac1、IGF - 1（胰岛素样生长因子1）受体、Akt和Erk1/2（细胞外信号调节激酶1/2）的活性下调。 这些发现不仅确定了mXinβ在闰盘成熟中的重要作用，还揭示了mXinβ调节N -钙黏蛋白介导的黏附信号及其在出生后心脏生长和动物存活中的串扰信号的机制。