Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Assistant Professor Timothy J. Mead, Case Western Reserve University, USA
- Second opponent: Assistant Professor Christine Chuang, University of Copenhagen, Denmark
- Third member and chair of the evaluation committee: Professor Henrik Schirmer, University of Oslo
Chair of the Defence
Associate Professor Kjetil Wessel Andressen, University of Oslo
Principal Supervisor
Professor Mathis Korseberg Stokke, University of Oslo
Summary
Heart failure is a leading cause of death worldwide. Patients with heart failure often have a stiffer heart than healthy individuals, which prevents the heart from functioning normally. This increased stiffness is mainly caused by excessive accumulation of extracellular matrix, termed cardiac fibrosis. There is currently no treatment targeting cardiac fibrosis, and better understanding of the molecular mechanisms that underlie this process is essential to develop new treatments.
In this thesis, we aim to provide a basis for improved treatment of patients with stiff hearts through increased understanding of fibrosis development. Specifically, we wanted to better understand the role of the proteoglycan versican in this process and to test the therapeutic potential of targeting an enzyme called a disintegrin and metalloprotease with thrombospondin motif 4 (ADAMTS4) enzyme in rats.
Using a pressure overload model, we found that versican is increased and cleaved into small pieces during the early phase of cardiac fibrosis development. Thus, we hypothesized that versican or its fragments induce a persistent inflammatory response that leads to the development of cardiac fibrosis and dysfunction. Employing conditional knockout mouse models and cell cultures, we found that reducing versican and its fragments attenuated inflammation and fibrosis and improved cardiac function. Notably, fragments containing the C-terminal domain were identified as key drivers of inflammation and fibrosis. The findings underpin inhibition of versican cleavage as a new anti-fibrotic strategy. Consistent with this, we also demonstrated that ADAMTS4 inhibition is beneficial for the heart subjected to pressure overload, potentially by controlling TGF-β availability and reducing versican cleavage.
Overall, our findings provide new insights into the molecular mechanisms contributing to cardiac fibrosis and suggest ADAMTS4 inhibition as a potential anti-fibrotic therapy.
Additional information
Contact the research support staff.