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Am J Physiol Heart Circ Physiol (August 31, 2007). doi:10.1152/ajpheart.00806.2007
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Submitted on July 11, 2007
Accepted on August 27, 2007

Loss of mXin{alpha}, an intercalated disc protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects

Elisabeth A Gustafson-Wagner1, Haley W Sinn1, Yen-Lin Chen2, Da-Zhi Wang3, Rebecca S Reiter1, Jenny Li-Chun Lin1, Baoli Yang4, Roger A. Williamson5, Ju Chen6, Cheng-I Lin7, and Jim Jung-Ching Lin8*

1 Biological Sciences, University of Iowa, Iowa City, Iowa, United States
2 Institutes of Physiology, Pahrmacology and Life Sciences, National Defense Medical Center, Taipei, Taiwan, Taiwan - Republic of China
3 Cell and Developmental Biology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States; Carolina Cardiovascular Biology Center, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, United States
4 Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, United States
5 Department of Obstetrics and Gynecology, University of Iowa College of Medicine, Iowa City,, Iowa, United States
6 Medicine, Univ. California San Diego, San Diego, California, United States; Univ. California San Diego
7 National Defense Medical Center, Institute of Physiology, Taipei, Taiwn, Taiwan - Republic of China
8 Biological Sciences, University pf Iowa, Iowa City, Iowa, United States

* To whom correspondence should be addressed. E-mail: jim-lin{at}uiowa.edu.

The intercalated disc protein, Xin, was originally discovered in chicken striated muscle and implicated in cardiac morphogenesis. In the mouse, there are two homologous genes, mXin{alpha} and mXin{beta}. The human homolog of mXin{alpha}, Cmya1, maps to chromosomal region 3p21.2-21.3, near a dilated cardiomyopathy with conduction defect-2 locus. Here, we report that mXin{alpha}-null mouse hearts are hypertrophied and exhibit fibrosis, indicative of cardiomyopathy. A significant upregulation of mXin{beta} likely provides partial compensation and accounts for the viability of the mXin{alpha}-null mice. Ultrastructural studies of mXin{alpha}-null mouse hearts reveal intercalated disc disruption and myofilament disarray. In mXin{alpha}-null mice, there is a significant decrease in the expression level of p120ctn, {beta}-catenin, N-cadherin, and desmoplakin, which could compromise the integrity of the intercalated discs and functionally weaken adhesion, leading to cardiac defects. Additionally, altered localization and decreased expression of connexin 43 is observed in the mXin{alpha}-null mouse heart, which together with previously observed abnormal electrophysiological properties of mXin{alpha}-deficient mouse ventricular myocytes, could potentially lead to conduction defects. Indeed, ECG recordings on the isolated perfused hearts (Langendorff's preparations) show a significantly prolonged QT interval in mXin{alpha}-deficient hearts. Thus, mXin{alpha} functions in regulating the hypertrophic response and maintaining the structural integrity of the intercalated disc in normal mice, likely through its association with adherens junctional components and actin cytoskeleton. The mXin{alpha} knockout mouse line provides a novel model of cardiac hypertrophy and cardiomyopathy with conduction defects.




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