Msc Karoline Bjarnesdatter Rypdal at Institute of Clinical Medicine will be defending the thesis “Connective tissue disorders and cardiac fibrosis: Genetic substrate and roles of ADAMTSL2 and ADAMTSL3 in the failing heart” for the degree of PhD (Philosophiae Doctor).
Chair of the Defence
Professor II Finn Olav Levy, University of Oslo
Group Leader and Researcher Ida G. Lunde, University of Oslo
Genetic variants in connective tissue proteins can cause heritable disorders, often affecting the cardiovascular system, and heart failure is a frequent cause of death in these patients.
In the present work, Rypdal and colleagues sought to evaluate high throughput DNA sequencing as a diagnostic service for patients with suspected hereditary connective tissue disorders, and elucidate the role of the connective tissue proteins, ADAMTSLs, in heart disease.
The researchers identified significant challenges in the interpretation of genetic variants in connective tissue proteins, and the diagnostic yield was limited, reaching only 9%. Yet, symptoms from the cardiovascular system was a good indication for high throughput sequencing.
During cardiac disease and heart failure, the connective tissue expands, often causing pathological cardiac fibrosis with increased risk of mortality. The researchers found that ADAMTSL family of connective tissue proteins plays a role in the failing heart, and has anti-fibrotic effects. Furthermore, they found that ADAMTSL3 had a cardio-protective role. By switching off the Adamtsl3 gene in a novel knock-out mouse model, and giving the mice heart failure, it was discovered that ADAMTSL3 was critical for survival and maintaining cardiac function.
To elucidate the ADAMTSL proteins’ function in the connective tissue of the heart, ADAMTSL2 and ADAMTSL3 were overexpressed in cardiac cells in the lab. Both proteins showed anti-fibrotic effects by limiting the pro-fibrotic signaling processes of the cells, causing a change in cell-type characteristic, from a heart failure and fibrosis phenotype, to a more quiescent stage. The researchers conclude that ADAMTSL proteins are novel molecular players in heart disease, with anti-fibrotic and cardio-protective roles.
March 18, 2022 10:15 AM, Runde Auditorium, Domus Medica