Targeting a new fibrosis pathway to improve prediction and therapy in heart failure
Heart failure (HF) is a common cardiovascular condition that leads to substantial morbidity and mortality. Although major advancements have been made in HF therapy, morbidity and mortality remain high, particularly in HF with preserved ejection fraction, for which therapeutic options are extremely limited. Myocardial fibrosis is one of the most prominent pathological changes in HF and a promising target for HF prevention and therapy.
We hypothesize that sphingosine-1-phosphate (S1P)-S1P receptor 3 (S1P3), a potent proinflammatory and profibrotic pathway, may play a critical role in this process. Our major goals are to elucidate the role of S1P-S1P3-driven pathways in HF and to develop a novel therapy, based on S1P3 blockade, to alleviate cardiac remodelling and HF.
Project objectives are to: (1) Investigate S1P3 blockade as a potential novel therapy for HF – We will assess whether S1P3 inhibition dampens cardiac inflammation and fibrosis and ameliorates HF in two in vivo rat models, as well as in vitro. (2) Explore the contribution of S1P-S1P3-driven pathways to HF pathogenesis – We will use a combination of transcriptomic, histological, and protein expression studies to investigate the role of S1P-S1P3 in cardiac remodelling and HF in two experimental models. The results will be validated in human myocardium. (3) Investigate S1P as predictive biomarker of major cardiovascular events and response to cardiac resynchronization therapy in HF patients.