Poster Presentation ESA-SRB 2023 in conjunction with ENSA

Adverse Cardiac Remodelling Following Foxe1 Deletion in the Adult Mouse (#225)

Alexander Widiapradja 1 , Martyn Bullock 2 3 , Grace Lim 2 3 , Roderick J Clifton-Bligh 2 3 4 , Scott P Levick 1
  1. Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, WV, USA
  2. Cancer Genetic Laboratory, Kolling Institute, St Leonards, NSW, Australia
  3. University of Sydney, Sydney, NSW, Australia
  4. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia

Cardiovascular disease, encompassing conditions such as heart failure with diastolic dysfunction, is a leading cause of mortality in adult populations of Australia and the United States. Diastolic dysfunction, characterized by the heart's failure to relax properly, is often associated with cardiac fibrosis, which is marked by excessive deposition of extracellular matrix components like collagen. Currently, there is a lack of effective targeted treatments for heart failure and the underlying fibrosis, underscoring an urgent need to explore novel therapeutic avenues for prevention and regression. In this context, our research investigates the FOXE1 gene, which encodes a transcription factor vital for thyroid gland development and function. While its extrathyroidal function remains largely unexplored, our study of a novel tamoxifen-induced Foxe1 knockout mouse model has revealed that the Foxe1 loss leads to adverse cardiac remodelling, including fibrosis. 

We hypothesized that a loss of Foxe1 promotes a pro-inflammatory macrophage state that induces a pro-fibrotic phenotype change in cardiac fibroblasts to ultimately cause fibrosis. 

Immunohistochemical (IHC) staining revealed a 10% increase (P<0.05) in collagen volume in Foxe1flox/flox/Cre mouse hearts compared to Cre controls (n=10 per group), harvested at 20 weeks post-tamoxifen treatment. Additionally, we observed a 60% increase (P<0.05) in pro-inflammatory (M1) macrophages and a 90% reduction (P<0.05) in anti-inflammatory (M2) macrophages. Consequently, the overall M1/M2 macrophage ratio was markedly reduced in Foxe1flox/flox/Cre hearts. Immunoblotting and IHC further detected Foxe1 nuclear staining in the Cre hearts, but not in the Foxe1flox/flox/Cre hearts.

Collectively, these findings constitute the first evidence that Foxe1 plays a cardio-protective role, specifically opposing cardiac inflammation and fibrosis. While the loss of Foxe1 shows detrimental effects on the heart, the cellular mechanisms underlying how Foxe1 loss impacts the phenotype of cardiac fibroblasts and macrophages remain to be elucidated. These insights may pave the way for innovative interventions against cardiac fibrosis.