Exploring the role of Wnt signalling in heart failure with preserved ejection fraction.

Paul, Mhairi A.

Abstract

According to the European Society of Cardiology long-term out-patient registry, heart failure with preserved ejection fraction (HFpEF) accounts for approximately 16% of heart failure cases, with survival rates failing to improve due to the lack of effective treatments and the increasing prevalence of co-morbidities. It has been widely documented throughout the literature that Wingless/int1 (Wnt) signalling plays a role in the development of both cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Useful in vivo models of HFpEF are lacking; however, a recently-published 'two-hit' (metabolic and mechanical stress) in vivo model of HFpEF shows promise. Targeting Wnt signalling as a potential therapeutic intervention in this HFpEF model has not yet been investigated, so the present study was therefore carried out in order to investigate whether pharmacological inhibition of Wnt signalling could improve detrimental structural and/or functional changes associated with HFpEF. The present study aimed to: 1) examine the role of Wnt signalling in cardiomyocyte hypertrophy; 2) investigate whether Wnt signalling contributes to the development of HFpEF using an in vivo model of the condition; and 3) determine whether the administration of a Wnt inhibitor (Wnt-c59) alters the maladaptive structural and/or functional changes associated with HFpEF. Initial in vitro experiments using H9c2 cells determined the optimum experimental conditions for AngII (1μM)-induced cardiomyocyte hypertrophy. Furthermore, subsequent experiments determined that AngII-induced cardiomyocyte hypertrophy is mediated, at least in part, via activation of canonical Wnt signalling; this thesis is the first to demonstrate this pro-hypertrophic pathway in human cardiomyocytes. A role for Wnt signalling in the pathogenesis of HFpEF (a condition characterised by cardiac hypertrophy) was then examined in an in vivo model of the condition, induced by the chronic administration of a high fat diet and Nω-nitro-L-arginine methyl ester (L-NAME; 0.5g/L) to mice for 7 weeks. Findings from this study demonstrated that this mouse model of HFpEF was characterised by hypertension, cardiac hypertrophy and fibrosis, diastolic dysfunction (measured via pressure volume loop analysis), but there was no evidence demonstrating activation of canonical Wnt signalling in the hearts of these animals. Thus, on the basis of this study, a role for canonical Wnt signalling in the development of HFpEF is not supported. Notwithstanding this, treatment of HFpEF mice with Wnt-c59 (5mg/kg/day) did ameliorate diastolic dysfunction via mechanisms that may contribute to increased ventricular compliance, such as BNP-induced phosphorylation of titin and/or favourable regulation of the ratio of collagen subtype expression. However, this requires further investigation. In conclusion, this study has identified a hypertrophic role for Wnt signalling in vitro, indicating a link between renin angiotensin-aldosterone system (RAAS) activation and the initiation of Wnt signalling. Furthermore, in the 'two-hit' model of HFpEF there was no evidence of activation of canonical Wnt signalling; however, treatment of HFpEF mice with Wnt-c59 did ameliorate diastolic dysfunction via mechanisms that may contribute to increased ventricular compliance.

Citation

PAUL, M.A. 2022. Exploring the role of Wnt signalling in heart failure with preserved ejection fraction. Robert Gordon University, PhD thesis. Hosted on OpenAIR [online]. Available from: https://doi.org/10.48526/rgu-wt-1987960

• Thesis Type: Thesis
• Deposit Date: Jun 15, 2023
• Publicly Available Date: Jun 15, 2023
• DOI: https://doi.org/10.48526/rgu-wt-1987960
• Keywords: Heart failure; Heart failure with preserved ejection fraction (HFpEF); Wnt signalling; Hypertension; Cardiac function
• Public URL: https://rgu-repository.worktribe.com/output/1987960
• Award Date: Mar 31, 2022