In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)
Abstract:
The role of β-catenin and the actions of 17β-estradiol (E2) in cardiovascular (patho)physiology remain unclear. In the diseased heart, E2 is expected to be cardioprotective. However, in the absence of prior disease, complications in pregnancy or transgender individuals indicate that E2 might lead to cardiovascular disease. We aimed at the characterization of the effects of the E2/β-catenin axis in the healthy C57Bl/6N heart. Two-month-old female C57Bl/6N wild-type (WT) and cardiac-specific β-catenin-deleted (β-cat Δex2-6 ) mice were ovariectomized and randomized to an E2-containing or soy-free (control, CON) diet ( n = 7-13/group). The 3-month physiological dose of E2 led to a significant repression of nuclear β-catenin levels vs. CON ( P 〈 0.001) in WT mice. This was underlain by a significant decrease in the heart weight to tibia length ratio and cardiomyocyte cross-sectional area (E2 vs. CON WT mice P 〈 0.001). Echocardiography revealed a significant decrease in septum width ( P 〈 0.001), posterior wall thickness ( P 〈 0.01) and fractional shortening ( P 〈 0.05) in E2 vs. CON WT mice. Deletion of β-catenin abrogated these E2-mediated deleterious effects on cardiac structure and function. Mechanistically, we found a significant increase in the levels of the ubiquitin ligase and key regulator of proteasome-dependent protein degradation muscle-specific RING finger protein 1 (MuRF1) in E2 vs. CON WT mice ( P 〈 0.05), while there was no effect in β-cat Δex2-6 mice. Although we also hypothesized increased autophagic activity, we found no effect on the autophagy-related protein LC3 in WT or β-cat Δex2-6 mice. In a translational approach, we profiled the left ventricular transcriptome of female patients ( n = 5) with end-stage non-ischemic dilated cardiomyopathy (DCM) vs. healthy controls ( n = 8). We found a significant induction in the expression of the genes coding for SFRP5 , a negative regulator of Wnt signaling, DACT2 , an antagonist of β-catenin, and APC2 , which is required for targeted degradation of β-catenin ( P 〈 0.01), in DCM samples. Our mouse data indicate that repression but not deletion of β-catenin leads to heart failure and our human data suggest that targeting Wnt/β-catenin signaling in heart failure may be of therapeutic value.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.119.suppl_1.400
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2016
detail.hit.zdb_id:
1467838-X
