Cardiac fibroblast as target for novel therapy in heart failure with a preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasing in prevalence and is associated with high morbidity and mortality. The quest for an effective therapy for established HFpEF has been widely acknowledged as one of the most pressing challenges in cardiovascular (CV) medicine. Myocardial fibrosis is a pivotal player in HFpEF development and progression and has complex pathophysiology; primarily driven by cardiac fibroblasts (cFBs)—an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix (ECM), but for which information is lacking. Our limited understanding of the biology of cFBs impedes the development of potential therapies targeting them and their pathological contribution to HFpEF progression. In the fibrotic response, fibroblasts are activated into myofibroblasts which mediate ECM production and tissue remodelling. The exact precursor of myofibroblasts remains an area of controversy. For example, our group previously showed that in contrast to previous theories, the majority of cFBs are not derived from bone marrow in HF. The limited availability of specific fibroblast markers has impeded progress in this field. Using a comprehensive lineage tracing approach confirmed that resident cardiac fibroblasts are critical determinant of cardiac fibroblast development and progression, thus providing a unique opportunity to study how cFBs are activated in disease. The role of cFBs in the development and progression of HFpEF has not been studied. Studies in cFBs suggest a role for key protein kinases in fibrosis in several CV disease paradigms, however, the true in vivo cellular biology is not well understood as the majority of studies are based on cell culture studies. We have developed novel compound that shows anti-fibrotic and anti-inflammatory effects in post-myocardial ischemic-reperfusion providing a useful pharmacological tool to explore the fibrosis process involving cFBs in HFpEF. Project Aims: This project is aimed to investigate the roles cardiac fibroblasts play in the development and progression of HFpEF using the transgenic mouse model. The study also aims investigate the efficacy of targeting fibroblast mesenchymal transition as a novel therapy for HFpEF. Techniques: It is anticipated that this study will involve the use of animal models in mice, cardiac function measurement with echocardiography and pressure-volume relationship analysis, Western blotting, immunohistochemistry, and gene expression analysis with PCR.