Disputation: Arne Olav Melleby
MSc Arne Olav Melleby at Institute of Clinical Medicine will be defending the thesis “Cardiac remodeling responses to increased afterload: Roles and regulation of cell surface proteoglycans and integrins” for the degree of PhD (Philosophiae Doctor).
Trial Lecture – time and place
See Trial Lecture.
- First opponent: Associate Professor Inês Falcâo Pires, University of Porto
- Second opponent: Senior Consultant Jørgen Gravning, Oslo University Hospital
- Third member and chair of the evaluation committee: Professor Kåre-Olav Stensløkken, University of Oslo
Chair of the Defence
Professor Finn Olav Levy, University of Oslo
Adviser Ida Gjervold Lunde, University of Oslo
Heart failure is a main cause of morbidity and mortality globally. Increased left ventricular afterload, or pressure overload, induces cardiac remodeling and failure, and mimicking heart failure experimentally is important to understand underlying disease mechanisms. The three studies included in this thesis introduce a novel method for increasing LV afterload in mice and explore how specific cell surface proteins regulate remodeling processes in the heart.
By using o-rings with specific inner diameters we created a new technique of aortic constriction, a commonly used technique for inducing pressure overload in preclinical models of heart failure. By applying o-rings with different inner diameters we produced specific cardiac phenotypes in mice mimicking the heart failure disease spectrum in a reproducible manner. Using biopsies from human hearts, knock-out mouse models and cultured cardiac fibroblasts and myocytes, we found that the investigated cell surface receptors affected cardiac remodeling. We found that glypican-6, a cell membrane-tethered co-receptor and proteoglycan, was upregulated in preclinical and clinical heart failure, and showed that increased glypican-6 levels induced hypertrophic growth in cardiomyocytes through activation of ERK signaling. In mice, we showed that there is upregulation of the cell surface mechanoreceptors syndecan-4 and integrin alpha11beta1 following pressure overload, and that cardiac hypertrophy and fibrosis can be attenuated through simultaneous ablation of both of these proteins.
In summary, the results presented in this thesis highlight novel roles for cell surface proteoglycans and integrins in cardiac remodeling after pressure overload. Moreover, our results emphasize the significance of precise and reproducible experimental models in translational research, which is important in the overall research effort towards developing new drugs for heart failure.
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