Abstract 2186: Loss Of Sfrp-1 Increases Nuclear Translocation of Beta-Catenin and Thioredoxin in the Heart Leading to Dilated Cardiomyopathy
Secreted frizzled related proteins (sFRPs) inhibit the Wnt pathway which is critical for wound healing post myocardial infarction, cardiac hypertrophy and vascular angiogenesis. To understand the role of sFRP-1 in the heart, mice lacking the sFRP-1 gene were followed over a course of one year and compared to age-matched littermate wild-type mice (WT). As previously reported, the hearts of the sFRP-1 knockout (KO) mice were normal at three months of age; however, at 6 months of age, the KO mice developed hypertrophic changes with an increase in the heart/body weight and LV posterior wall thickness compared to age-matched WT mice. Furthermore, at one year of age, the KO mice developed LV chamber dilation when compared to WT mice with worsened LV systolic function and decreased diastolic function. There was increased interstitial and perivascular fibrosis in the KO mice at one year of age without change in proliferation. To determine how sFRP-1 impacted on signaling pathways linked to cardiac hypertrophy and failure, heart tissue of three month and one year old KO and WT mice was compartmentalized into cytosolic and nuclear fractions and analyzed for changes in MAPK activation, Wnt and thioredoxin signaling. Loss of sFRP-1 in the heart had no effect on MAPK proteins (p38, ERK, JNK); however, it significantly increased nuclear translocation of β-catenin and thioredoxin both at 3 months and 1 year of age. Coincident with the development of cardiac failure, increased levels of reactive nitrogen species (RNS) were observed at 1 year in the KO compared to WT mice (KO/n=6, 3.2 ±0.34 vs. WT/n=8, 2.2 ±0.30, p=0.0136). This study demonstrates for the first time that sFRP-1 regulates nuclear translocation of beta-catenin and thioredoxin in the heart, two key transcriptional regulators that have been linked to heart failure. These altered signaling events predate the development of cardiac decompensation and increased oxidative stress. Future studies will examine the downstream targets of beta-catenin and thioredoxin that mediate these physiologic changes. Further understanding the role of sFRP-1 in the heart and how it regulates the Wnt signaling and antioxidants may elucidate new insights into novel therapeutic targets in the management of heart failure patients.