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: Professor Nikos Karamanos, University of Patras, Greece
- Second opponent: Associate Professor Neoma Tove Boardman, UiT The Arctic University of Norway
- Third member and chair of the evaluation committee: Professor Finn Olav Levy, University of Oslo
Chair of the Defence
Professor Kåre Olav Stensløkken, University of Oslo
Principal Supervisor
Professor II Ida Gjervold Lunde, University of Oslo
Summary
Heart failure is a global health issue. This thesis aimed to investigate underlying molecular mechanisms and potential treatments for heart failure, using translational in vivo and in vitro models.
A common comorbidity of heart failure is metabolic syndrome, which is associated with heart failure with preserved ejection fraction (HFpEF), both of which involve the endothelium. In article I, we investigated a rat model of metabolic syndrome leading to HFpEF and the effectiveness of macitentan therapy, a dual endothelin receptor antagonist. Macitentan improved cardiac function and remodelling. This treatment also improved systolic and diastolic blood pressure and coronary relaxation. Further to this, the effect of selenoprotein T (SELENOT), key for redox regulation and maintenance of the endothelium, was explored in article II. A rat model of myocardial infarction was used to model heart failure with reduced ejection fraction (HFrEF). SELENOT therapy was induced by viral vectors, either systemically in the circulation or expressed intracellularly in the cardiac tissue. SELENOT circulating and cardiac intracellular induction reduced ischemic injury and restored cardiac function. Cardiac remodelling and vascular relaxation were also improved. In article III, to assess myocardial fibrosis, a key pathophysiological process in heart failure, human foetal cardiac fibroblasts (hfCFBs) and mouse embryonic fibroblasts cell lines (MEFs) were investigated in vitro. We specifically investigated the role of syndecan-4, a transmembrane proteoglycan, in myofibroblast differentiation. Syndecan-4 was shown to have a protective effect in hfCFBs and MEFs against myofibroblast differentiation. This was demonstrated by an increase in alpha smooth muscle actin production when there was a lack of syndecan-4.
Overall, these results provide insight into underlying heart failure molecular mechanisms and the benefits of new potential therapies.
Additional information
Contact the research support staff.