Proteoglycan Signaling Induces Myocardial Fibrosis and Diastolic Heart Failure

Heart failure is a major killer in Western world countries, estimated to be present in 2-3% of the population. Reduced filling of the heart is an important cause of heart failure, and is mainly due to a stiffer heart caused by increased connective tissue and fibrosis. There is currently no effective medical treatment for fibrosis in the heart, suggesting that important disease mechanisms remain unknown and that there is need for more specific drug targets. We have in this project period examined the proteoglycans lumican, fibromodulin, syndecan and versican in the heart, and found that these molecules are important regulators of structure and function during development of heart disease. Since our last report submitted in October and until termination of the project December 31 the project has proceeded in accordance with the plans in the application. Our recent results show that several of the proteoglycans studied have an active and central role in determining extracellular matrix and filling of the heart. We plan to submit five articles from this project in 2019. Furthermore, important data have been obtained showing that inhibition of turnover of proteoglycans improves cardiac function and reduces fibrosis. These new exciting data indicate that inhibition of proteoglycan degradation may represent a new therapeutic strategy for treatment of heart failure. Planning of patient studies has been completed, and collaboration with pharmaceutical companies and Inven2 is ongoing. We will continue our investigations of the role of cardiac proteoglycans in regulating stiffness of the heart in accordance with the proposed project plan. Importantly, the discovery of beneficial effects of inhibition of degradation of cardiac proteoglycans may lead to a whole range of novel targets in heart failure therapy. This project is conducted at Institute for Experimental Medical Research together with Department of Thoracic Surgery and Department of Cardiology, Oslo University Hospital and scientists from Harvard, Johns Hopkins and Lund University.

Prosjektet har ført til betydelig økt kompetanse innen forskningsgruppen og vært med på å legge grunnlaget for viktig karriereutvikling for unge lovende kvinnelige forskere. Eksempelvis fikk en av deltagerne i prosjektperioden tildelt stipendiet Unge forskertalenter fra Norges forskningsråd. Andre deltagere i prosjektet har fått selvstendige postdocstipend og fire PhD kandidater vil kort tid etter avslutning av dette prosjektet sende inn sine doktorgradsarbeider. I prosjektperioden har det vært en betydelig videreutvikling av internasjonalt samarbeid med grupper i Europa og USA. De vitenskapelige funnene har vært presentert på en rekke konferanser og fått priser for beste arbeider. Langsiktige effekter på samfunnsnivå som følge av våre resultater kan bli betydelige siden vi nå har fått godkjent patentkrav på en ny behandlingsform for hjertesvikt. Denne behandlingen har vist svært gode effekter i prekliniske studier. Planer og finansiering for en klinisk studie er nå klare.

Heart failure is a major killer in Western world countries, estimated to be present in 2-3% of the population. Diastolic dysfunction is reflected in reduced end-diastolic volume, mainly due to a stiffer myocardium caused by extracellular matrix (ECM) remodeling and myocardial fibrosis. There is currently no effective medical treatment for myocardial fibrosis, suggesting that important pathological mechanisms remain unknown and that there is need for more specific targets. We here introduce the concept of cardiac proteoglycans being active and central mediators of myocardial fibrosis. Proteoglycans are highly glycosylated proteins localized in the ECM or bound to cell membranes. Traditionally, proteoglycans are considered mainly to be structural molecules of connective tissues and studies in the heart are sparse. Exciting new results from our lab indicate an active role for proteoglycans in determining diastolic function. We have recently shown that the membrane-bound proteoglycan, syndecan-4 acts as a mechanical stress-sensor in cardiac fibroblasts inducing down-stream pro-fibrotic signaling resulting in increased myocardial stiffness. Furthermore, the ECM-localized proteoglycan lumican was found to have a direct effect on cardiac fibroblast activity triggering pro-fibrotic signaling. Based on these findings we wish to investigate the role of cardiac proteoglycans in regulating myocardial stiffness by actively inducing pro-fibrotic responses of cardiac fibroblasts following mechanical stress. Importantly, the discovery of active signaling roles for cardiac proteoglycans may lead to a whole range of novel targets in heart failure therapy. This project will be conducted at Institute for Experimental Medical Research together with Dept of Thoracic Surgery and Dept of Cardiology, Oslo University Hospital and scientists from Harvard, Johns Hopkins and Lund University.