Essential Roles of an Intercalated Disc Protein, mXinβ, in Postnatal Heart Growth and Survival

被引:32
作者
Wang, Qinchuan [1 ]
Lin, Jenny Li-Chun [1 ]
Reinking, Benjamin E. [2 ]
Feng, Han-Zhong [4 ]
Chan, Fu-Chi [5 ]
Lin, Cheng-I [5 ]
Jin, Jian-Ping [4 ]
Gustafson-Wagner, Elisabeth A. [1 ]
Scholz, Thomas D. [2 ]
Yang, Baoli [3 ]
Lin, Jim Jung-Ching [1 ]
机构
[1] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA
[2] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA
[3] Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA
[4] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA
[5] Natl Def Med Ctr, Inst Physiol, Taipei, Taiwan
关键词
N-cadherin-mediated adhesion signaling; Xin repeat-containing protein; intercalated disc maturation; diastolic dysfunction; postnatal heart growth; VENTRICULAR DIASTOLIC FUNCTION; RHO FAMILY GTPASES; CARDIAC-HYPERTROPHY; TROPONIN-I; E-CADHERIN; DEVELOPMENTAL-CHANGES; CONDUCTION DEFECTS; MOLECULAR SWITCH; GAP-JUNCTIONS; XIN;
D O I
10.1161/CIRCRESAHA.109.212787
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Rationale: The Xin repeat-containing proteins mXin alpha and mXin beta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXin alpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXin alpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXin beta in mXin alpha-deficient hearts suggests a partial compensation. Objective: The essential roles of mXin beta in cardiac development and intercalated disc maturation were investigated. Methods and Results: Ablation of mXin beta led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXin alpha. Postnatal upregulation of mXin beta in wild-type hearts, as well as altered apoptosis and proliferation in mXin beta-null hearts, suggests that mXin beta is required for postnatal heart remodeling. The mXin beta-null hearts exhibited a misorganized 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 mXin beta resulted in the failure of forming mature intercalated discs and the mislocalization of mXin alpha and N-cadherin. The mXin beta-null hearts showed upregulation of active Stat3 (signal transducer and activator of transcription 3) and downregulation of the activities of Rac1, insulin-like growth factor 1 receptor, protein kinase B, and extracellular signal-regulated kinases 1 and 2. Conclusions: These findings identify not only an essential role of mXin beta in the intercalated disc maturation but also mechanisms of mXin beta modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival. (Circ Res. 2010; 106:1468-1478.)
引用
收藏
页码:1468 / U61
页数:31
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