WNT/BETACANTENIN SIGNALING AND CARDIAC ION CHANNELS

University Of Washington, Seattle WA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): 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 ß-catenin and FoxO interaction to enhance the expression of the target genes. Canonical Wnt/ß-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/ß-catenin pathway decreases ß-catenin phosphorylation by CK- 1ß and GSK-3ß 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-3ß inhibitors, lithium chloride and BIO or overexpression of activated ß-catenin led to decreased NaV1.5 expression. We also found that expression of constitutively active GSK-3ßS9A decreased ß-catenin and increased NaV1.5 expression in HL-1 cardiomyocytes. We hypothesize that activation of Wnt/ß-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 ß-catenin in the regulation of NaV1.5 expression in mouse hearts; AIM 2: To determine the molecular mechanisms of ß-catenin suppressing NaV1.5 expression in mouse hearts; AIM 3: To determine if ß-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, ß- 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 ß-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.