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


ABSTRACT:

Rationale

The Xin repeat-containing proteins mXinalpha and mXinbeta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinalpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXinalpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinbeta in mXinalpha-deficient hearts suggests a partial compensation.

Objective

The essential roles of mXinbeta in cardiac development and intercalated disc maturation were investigated.

Methods and results

Ablation of mXinbeta led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinalpha. Postnatal upregulation of mXinbeta in wild-type hearts, as well as altered apoptosis and proliferation in mXinbeta-null hearts, suggests that mXinbeta is required for postnatal heart remodeling. The mXinbeta-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 mXinbeta resulted in the failure of forming mature intercalated discs and the mislocalization of mXinalpha and N-cadherin. The mXinbeta-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 mXinbeta in the intercalated disc maturation but also mechanisms of mXinbeta modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.

SUBMITTER: Wang Q 

PROVIDER: S-EPMC2872156 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Publications

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

Wang Qinchuan Q   Lin Jenny Li-Chun JL   Reinking Benjamin E BE   Feng Han-Zhong HZ   Chan Fu-Chi FC   Lin Cheng-I CI   Jin Jian-Ping JP   Gustafson-Wagner Elisabeth A EA   Scholz Thomas D TD   Yang Baoli B   Lin Jim Jung-Ching JJ  

Circulation research 20100401 9


<h4>Rationale</h4>The Xin repeat-containing proteins mXinalpha and mXinbeta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinalpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXinalpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinbeta in mXinalpha-deficient hearts suggests a partial compensation.<h4>Objective</h4>The essential roles of mXinbet  ...[more]

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