Arne Olav Melleby‘s PhD thesis explores how specific cell surface proteins regulate remodelling processes in the heart.
- Glypican-6 is expressed in the heart, and levels are increased in heart failure.
- Syndecan-4 and integrin α11 are required to induce cardiac hypertrophic remodelling.
- A novel method of aortic banding results in cardiac hypertrophy with very low mortality.
Thesis: Cardiac remodeling responses to increased afterload: Roles and regulation of cell surface proteoglycans and integrins
Candidate: Arne Olav Melleby
Time: June 3, 2020 at 11:15
Place: Online-based solution, due to the covid-19 situation
Link to university website
(1) Glypican-6 is elevated in explanted human and in failing mouse hearts. In the failing human hearts, higher levels of glypican-6 were linked to lower ejection fraction. In the mouse model, genetic expression of glypican-6 was associated with both the degree of left ventricular hypertrophic remodelling and the severity of heart failure.
The mice in the study were subjected to pressure overload by aortic banding. Cardiac remodeling started within the first few weeks, and 18 week after aortic banding the mice had developed dilated end-stage heart failure. The genetic expression of glypican-6 were almost doubled compared to healthy mice throughout the 18 weeks. The five other glypicans were not differently expressed in healthy and failing hearts.
Further experiments showed that glypican-6 is expressed in cardiomyocytes and cardiac fibroblasts. In cardiomyocytes, glypican-6 activates the signaling pathways ERK1 and ERK2, leading to pathological cardiac hypertrophy.
(3) Lack of integrin α11 and syndecan-4 protects against adverse remodelling following aortic banding. Following pressure overload in mice, both syndecan-4 and integrin α11 were required to induce cardiac hypertrophic remodelling.
(2) Melleby and co-workers also developed a novel model for increased mechanical strain on mice heart. By using o-rings with fixed inner diameter, they established a model of high precision aortic constriction, resulting in hypertrophy within one week and very low mortality.
(1) Melleby, A. O., Strand, M. E., Romaine, A., Herum, K. M., Skrbic, B., Dahl, C. P., Sjaastad, I., Fiane, A. E., Filmus, J., Christensen, G., & Lunde, I. G. (2016). The heparan sulfate proteoglycan glypican-6 is upregulated in the failing heart, and regulates cardiomyocyte growth through ERK1/2 signaling. PloS one, 11(10).
(2) Melleby, A. O., Romaine, A., Aronsen, J. M., Veras, I., Zhang, L., Sjaastad, I., Lunde, I. G., & Christensen, G. (2018). A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice. Cardiovascular research, 114(12), 1680-1690.