Alterations of ion channel activity play important roles in the development of cardiac arrhythmias. NaV1.5, encoded by the SCN5a gene, is a subunit of the cardiac Na+ channel, the activity of which determines cardiac excitability and electrical conduction. Decreased Na+ channel activity is linked to cardiac arrhythmias in different types of cardiac diseases, but it is largely unknown how this channel is transcriptionally regulated. FoxO1 mediates the inhibition of SCN5a promoter activity by oxidative stress, and oxidative stress promotes -catenin and FoxO interaction to enhance the expression of the target genes. Canonical Wnt/-catenin signaling is quiescent in the normal hearts. However, in the diseased hearts, this signaling pathway is activated while NaV1.5 expression and Na+ channel are inhibited, suggesting that this signaling pathway may involve the Na+ channel regulation. Activation of the Wnt/-catenin pathway decreases -catenin phosphorylation by CK- 1 and GSK-3 and promotes its interaction with transcriptional factors such as TCF4 and FoxO1 to regulate the target genes' expression. Our preliminary results showed that treatment with the GSK-3 inhibitors, lithium chloride and BIO or overexpression of activated -catenin led to decreased NaV1.5 expression. We also found that expression of constitutively active GSK-3S9A decreased -catenin and increased NaV1.5 expression in HL-1 cardiomyocytes. We hypothesize that activation of Wnt/-catenin signaling suppresses NaV1.5 expression by its interaction with TCF4 and FoxO1, leading to a decrease of Na+ channel activity, cardiac depolarization and cardiac conduction. We will test this hypothesis in the 3 specific aims as follows:
AIM 1 : To define the role of -catenin in the regulation of NaV1.5 expression in mouse hearts;
AIM 2 : To determine the molecular mechanisms of -catenin suppressing NaV1.5 expression in mouse hearts;
AIM 3 : To determine if -catenin-mediated inhibition of NaV1.5 expression in cardiomyocytes requires both FoxO1 and TCF4 for cardiac conduction regulation. In order to achieve these 3 specific AIMs, we will particularly use cardiac specific Cre-Lox technology and delete key Wnt signaling components such TCF4, - catenin, and APC, and FoxO1 transcriptional factor in mouse hearts. We will identify the alterations of NaV1.5 expression and Na+ channel activity and cardiac electrical remodeling in these genetically engineered mice. Our main anticipated finding is that -catenin, TCF4 and FoxO1 form a complex to suppress NaV1.5 expression by inhibiting the SCN5a promoter activity, leading to slowed cardiac depolarization and cardiac conduction. The proposed studies will identify a potential and novel therapeutic target for treatment of cardiac arrhythmias.

Public Health Relevance

Ischemic heart disease (IHD), where blood supply to the heart is reduced, is a common health problem, and cardiac arrhythmias are often associated with it. Some arrhythmias, such as ventricular tachycardia (where the heart beats dangerously fast) and ventricular fibrillation (where the heart muscle quivers uncontrollably) can be fatal. Studies have associated these arrhythmias with problems of sodium channel through heart cell membranes. Our study will investigate the role of Wnt/-catenin signaling usually activated in IHD in the regulation of sodium channel, with the hope that our studies of Wnt/-catenin signaling regulating the sodium channels may provide the basis for new therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122793-05
Application #
9456772
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hou, Ning; Wen, Ying; Yuan, Xun et al. (2017) Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp Mol Pathol 103:267-275
Wang, Ning; Huo, Rong; Cai, Benzhi et al. (2016) Activation of Wnt/?-catenin signaling by hydrogen peroxide transcriptionally inhibits NaV1.5 expression. Free Radic Biol Med 96:34-44
Hou, Ning; Ye, Bo; Li, Xiang et al. (2016) Transcription Factor 7-like 2 Mediates Canonical Wnt/?-Catenin Signaling and c-Myc Upregulation in Heart Failure. Circ Heart Fail 9:
Ye, Bo; Hou, Ning; Xiao, Lu et al. (2015) APC controls asymmetric Wnt/?-catenin signaling and cardiomyocyte proliferation gradient in the heart. J Mol Cell Cardiol 89:287-96
Ye, Bo; Ge, Yao; Perens, Gregory et al. (2013) Canonical Wnt/?-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction. Cardiovasc Pathol 22:54-7