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

Qinchuan Wang, Jenny Li Chun Lin, Benjamin E. Reinking, Han Zhong Feng, Fu Chi Chan, Cheng I. Lin, Jian Ping Jin, Elisabeth A. Gustafson-Wagner, Thomas D. Scholz, Baoli Yang, Jim Jung Ching Lin

Research output: Contribution to journalArticlepeer-review

Abstract

RATIONALE: The Xin repeat-containing proteins mXinα and mXinβ localize to the intercalated disc 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 cardiomyopathy with conduction defects. An upregulation of the mXinβ in mXinα-deficient hearts suggests a partial compensation. OBJECTIVE: The essential roles of mXinβ in cardiac development and intercalated disc maturation were investigated. METHODS AND RESULTS: Ablation of mXinβ led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinα. Postnatal upregulation of mXinβ in wild-type hearts, as well as altered apoptosis and proliferation in mXinβ-null hearts, suggests that mXinβ is required for postnatal heart remodeling. The mXinβ-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 mXinβ resulted in the failure of forming mature intercalated discs and the mislocalization of mXinα and N-cadherin. The mXinβ-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 mXinβ in the intercalated disc maturation but also mechanisms of mXinβ modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.

Original languageEnglish (US)
Pages (from-to)1468-1478
Number of pages11
JournalCirculation research
Volume106
Issue number9
DOIs
StatePublished - May 14 2010
Externally publishedYes

Keywords

  • Diastolic dysfunction
  • Intercalated disc maturation
  • N-cadherin-mediated adhesion signaling
  • Postnatal heart growth
  • Xin repeat-containing protein

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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