Trial Lecture – time and place
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Adjudication committee
- First opponent: Associate Professor Neil Turner, Leeds Institute of Cardiovascular & Metabolic Medicine (LICAMM), University of Leeds, UK
- Second opponent: Professor Staffan Johansson, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden
- Third member and chair of the evaluation committee: Professor Ingebjørg Seljeflot, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor Emeritus Harald Arnesen, Faculty of Medicine, University of Oslo
Principal Supervisor
Professor II Geir Christensen, Faculty of Medicine, University of Oslo
Summary
Heart failure remains a prevalent and debilitating condition in both low-income and high-income countries. Conditions such as high blood pressure can put added mechanical stress on the heart, which can trigger large-scale changes to the structure and function of the heart ultimately resulting in failure.
The aims of this thesis were to identify important cell sensors in the heart, which are responsive to increased mechanical stress, and to determine whether loss of these sensors would be protective.
Two families of cell surface mechanosensors are considered important across the body, the integrins and syndecans. To narrow down which members of the large integrin family are important in the cardiac remodelling process, we first measured their expression following induction of a cardiac insult. We found that one particular integrin, integrin alpha-11, was highly upregulated in disease. Importantly, we demonstrated that high expression of integrin alpha-11 alone led to cardiac remodelling.
Lacking the syndecan member syndecan-4 in addition to integrin alpha-11 resulted in protection from the adverse remodelling effects of aortic banding. Through the course of our investigations, we also developed an improved method for modelling increased left ventricular afterload. Finally, we demonstrated that syndecan-4 may also protects the heart from adverse remodelling by preventing the degradation of another protein, osteopontin.
Together, we identify two strong candidates for future therapeutic targeting of heart failure and also shed light on the complex molecular interactions that occur between members of the mechanosensing apparatus of the heart.
Additional information
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