Heart failure is the only cardiovascular disease with an increasing worldwide incidence1. Approximately 5 million people in the United States have heart failure, with over 550,000 diagnosed for the first time each year. Among heart diseases, failure due to arrhythmias is causing about 37,000 deaths in 2009 and the total estimated health care costs for arrhythmias in 2006 totaled 3.1 billion2. The molecular basis of arrhythmias is unclear, but Xin has been identified as being related to heart diseases3- 12. The mouse orthologs (mXina and mXinb) of human cardiomyopathy-associated genes (CMYA1 and CMYA3, respectively)9 encode proteins localized to the intercalated discs (ICDs). Mouse hearts deficient in mXina lead to adult late-onset cardiomyopathy with conduction defects and up-regulate mXinb, despite a normal appearance of ICD at young ages7. On the other hand, complete loss of mXinb results in failure of forming ICD, diastolic dysfunction, and early postnatal lethality4. The mXinb-null hearts exhibit mis-localization of mXina, and thus could lead to conduction defects and/or arrhythmias. Our long-term goal is to determine the molecular mechanisms by which mXin proteins influence the process of cardiac rhythms. We found that the mXina-null cardiomyocytes had reduced transient outward potassium (Ito) current density. Similar to Kv4.2 (a channel-forming subunit of Ito), mXina also interacted with Kv channel interacting protein 2 (KChIP2, an auxiliary subunit of Ito) and filamin (an actin crosslinking protein). Through these interactions, mXina may promote the surface expression of the Ito channel. Our working hypothesis is that in a functional hierarchy, mXinb plays essential role in controlling the localization of mXina, which, in turn, regulates the surface expression of Ito channel via its interactions with KChIP2 and filamin. In the Aim 1, we will establish the roles and the mechanisms by which mXina regulates the surface expression and functioning of Ito channels. We will define KChIP2 and filamin binding domains on mXina, generate uncoupled mutants, and test their effects on channel surface expression.
The Aim 2 is to establish the roles of mXinb in the ICD localizations of mXina and other ICD components in early postnatal and adult heart. We anticipate a functional hierarchy among mXinb, mXina, and ICD components, in their ICD localized actions. We will use inducible, cardiac-specific mXinb-null mice to test if mXinb is required for maintaining ICD assembly in adult heart. In the Aim 3, we will determine the role and the mechanisms by which mXinb regulates surface channel expression, action potential duration and then cardiac rhythm. Both mXina and mXinb represent relatively unexplored territories, despite their essential roles in the ICD formation and ion channel surface expression. Through these studies, we will advance our understanding of the mechanisms in the disease processes of arrhythmias and congestive heart failure and thus hope to identify novel, effective therapeutic targets.

Public Health Relevance

We investigate the roles of two mouse orthologs (mXina and mXinb) of human cardiomyopathy-associated genes, CMYA1 and CMYA3, respectively, in the process of cardiac rhythms. In a functional hierarchy, mXinb plays an essential role in determining the normal localization of mXina, which could then regulate surface expression and functioning of the transient outward potassium currents. Understanding these controlling mechanisms will advance our knowledge in the disease processes of arrhythmias and heart failure and thus hope to identify novel, effective therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107383-03
Application #
8442335
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Wang, Lan-Hsiang
Project Start
2011-05-18
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$357,521
Indirect Cost
$119,521
Name
University of Iowa
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Wang, Qinchuan; Lin, Jenny Li-Chun; Erives, Albert J et al. (2014) New insights into the roles of Xin repeat-containing proteins in cardiac development, function, and disease. Int Rev Cell Mol Biol 310:89-128
Wu, Adonis Zhi-Yang; Loh, Shih-Hurng; Cheng, Tzu-Hurng et al. (2013) Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes. Biochem Pharmacol 85:69-80
Feng, Han-Zhong; Wang, Qinchuan; Reiter, Rebecca S et al. (2013) Localization and function of Xin* in mouse skeletal muscle. Am J Physiol Cell Physiol 304:C1002-12
Wang, Qinchuan; Lin, Jenny Li-Chun; Chan, Stephen Y et al. (2013) The Xin repeat-containing protein, mXinýý, initiates the maturation of the intercalated discs during postnatal heart development. Dev Biol 374:264-80
Wang, Qinchuan; Lu, Te-Ling; Adams, Eric et al. (2013) Intercalated disc protein, mXinýý, suppresses p120-catenin-induced branching phenotype via its interactions with p120-catenin and cortactin. Arch Biochem Biophys 535:91-100
Chan, Fu-Chi; Cheng, Chiao-Pei; Wu, Kuo-Ho et al. (2011) Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes. Front Biosci (Elite Ed) 3:1425-42