The role of non-canonical WNT signaling in the development of atrial cardiomyopathy and atrial fibrillation

• Applicant: Fabienne Kreimer
• Subject Area: Cardiology, Angiology
• Term: Funded in 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534358899

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a rapidly growing prevalence that is expected to double in the next 30 years. The consequences of AF include higher rates of stroke, dementia, and congestive heart failure, and AF is even associated with increased mortality. New therapeutic options, particularly those with unique mechanisms of action, are needed to improve the treatment of patients with AF. Genetic studies of AF have identified a single nucleotide polymorphism (SNP) near the transcription factor ZFHX3 as the second most strongly associated gene variant. The SNP was found to modulate an enhancer that regulates ZFHX3 expression, and decreased ZFHX3 expression was found to increase the risk of AF. Cardiac Zfhx3 deficiency in mice has been shown to lead to early atrial structural/electrical pathology and eventually cardiomyopathy. WNT proteins are highly conserved growth factors that regulate cellular processes such as gene transcription, cell proliferation, migration, polarity, and division. WNT signaling is essential for cardiac development and is characterized by a canonical and a noncanonical pathway. Upregulation of the noncanonical WNT signaling pathway has been identified as a common and perhaps unifying feature in AF. However, there is a growing body of data suggesting "reactivation" of the WNT pathway in various cardiac diseases, and we suggest that this may be the case in both genetically predisposed and "acquired" AF. SFRP5 is an inhibitory WNT ligand and adipokine with affinity for the non-canonical WNT5a. ZFHX3 has been found to regulate the expression of SFRP5, such that ZFHX3 deficiency leads to increased WNT signaling. We will investigate whether non-canonical WNT inhibition by overexpression of SFRP5 can "rescue" the pathology associated with ZFHX3 knockout. The working hypothesis of the project is that pathological non-canonical WNT signaling contributes to AF susceptibility in both genetic and acquired AF and therefore may be a common pathway that can be exploited for therapeutic purposes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Patrick T. Ellinor