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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Elena Aikawa, Brigham and Women's Hospital, Harvard Medical School, US
- Second opponent: Assistant Professor Jesper Hjortnaes, Leiden University Medical Centre, The Netherlands
- Third member and chair of the evaluation committee: Professor Ida Gjervold Lunde, University of Oslo
Chair of the Defence
Professor Per Ole Iversen, University of Oslo
Principal Supervisor
Professor Kåre-Olav Stensløkken, University of Oslo
Summary
Calcific aortic valve disease (CAVD), the most prevalent valvular disorder in the elderly, causes aortic stenosis, heart failure, and death if untreated. With no pharmacological therapies available, valve replacement remains the only option. This thesis investigates the cellular and molecular mechanisms of human CAVD, focusing on valve interstitial cells (VICs) and valve endothelial cells (VECs) from stenotic and healthy valves of heart transplant recipients.
Four studies employed in vitro osteogenic induction, 2D and 3D VICs-VECs co-cultures, proteomics, and NMR metabolomics.
First, comparing six osteogenic media in VICs and bone marrow stem cells identified an optimal protocol and showed VICs are more responsive, making them the preferred in vitro model.
Addressing diabetes as a risk factor, high glucose (25 mM) reduced calcification by 52% versus physiological levels, revealing a negative dose-response. Hyperglycemia alone does not drive calcification; secondary effects – advanced glycation end-products, oxidative stress, and inflammation – likely play a pathogenetic role.
In co-cultures, VECs nearly doubled VICs calcification. VECs from calcified valves induced osteogenic differentiation in healthy VICs while suppressing myofibroblastic contraction. Proteomics revealed loss of structural and antioxidant proteins and upregulation of pro-inflammatory and remodeling proteins in diseased VECs. Notably, extracellular vesicles from VECs did not enhance calcification, suggesting direct VICs-VECs contact or paracrine signaling.
Metabolomic profiling showed reduced NAD+ and adenine nucleotides in VICs from calcified valves, indicating impaired mitochondrial energy production and predisposition to osteogenic differentiation.
These findings challenge traditional concepts and support an integrated CAVD model involving VECs dysfunction, intercellular communication, and metabolic reprogramming as therapeutic targets.
Additional information
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