Abstract 281: Loss of Krueppel-like Factor 15 (KLF15) Leads to Altered Wnt-dependent Gene Regulation in Hearts With Systolic Dysfunction

Abstract

Background & Aim: Developmentally conserved pathways, such as the Wnt/β-catenin pathway, are upregulated in adult heart diseases. Here, we aimed to elucidate the role of Wnt regulation via KLF15 for adult heart homeostasis. Results: We identified the transcription factor KLF15, a factor previously identified to contribute to cardiac fibrosis and hypertrophy, as a cardiac specific Wnt/β-catenin inhibitor. Accordingly, a constitutive Klf15 KO mouse model revealed specific cardiac upregulation of the Wnt target genes Tcf7l2 and cMyc (n=6, p<0.001). Serial echocardiography showed reduced systolic function starting at 16 weeks in the Klf15 KO hearts (n=10, p<0.05). Genome-wide sequencing studies of Klf15 KO vs. WT hearts at the postnatal age day P10, week 4 and 20 showed that gene expression differs increasingly at 4 and 20 weeks of age, respectively. This is in line with the increasing KLF15 expression after birth, reaching significant level at P13 (n=3/embryonal, fetal, and neonatal stage; each 5-8 pooled hearts). Accordingly, gene set enrichment analysis revealed activation of the Wnt signaling in Klf15 KO hearts at 4 and 20 weeks but not at P10 (p<0.001). This activation was milder in 20 weeks vs. 4 weeks, which may be explained by a concomitant upregulation of Wnt repressors, as Shisa3 and Dact3 with so far unknown function in the mammalian heart (n=9, p<0,01). Wnt activation was accompanied by upregulation of developmental genes and transcriptional regulators at 4 weeks and followed by upregulation of stress factors such as ANP, BNP, and Ankrd1 at 20 weeks. Moreover, we found the Wnt targets TCF7L2 and AXIN2 significantly upregulated in human ventricular biopsies from dilated (n≥5, p<0.05) and ischemic cardiomyopathy (n≥5, p<0.001) vs. non-failing, further underscoring the relevance of the Wnt pathway for human cardiac cellular homeostasis as well. Conclusion: A Wnt-dependent gene signature may precede the expression of stress factors and functional deterioration due to deletion of its cardiac repressor KLF15. Our data indicate that KLF15 is an important regulator of the Wnt pathway and is relevant for cardiac homeostasis and function in the postnatal heart.