Public Defence: May-Kristin Skaug Torp
M.Sc May-Kristin Skaug Torp at Institute of Basic Medical Science will be defending the thesis "Targeting innate immunity in ischemia-reperfusion of the heart" for the degree of Philosophiae doctor.
Foto: Alicia Del Prado
Trial lecture - time and place
See Trial lecture.
- First opponent: Professorial Research Fellow, Dr. Sean Davidson, Hatter Cardiovascular Institute, University College London, UK
- Second opponent: Professor Trude Helen Flo, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU, Norway
- Third member and chair of the evaluation committee: Researcher Cathrine Rein Carlson, Institute for Experimental Medical Research, Faculty of Medicine, University of Oslo
Chair of defence
- Professor Erik Dissen, Faculty of Medicine, University of Oslo
- Professor Kåre-Olav Stensløkken, University of Oslo
Acute myocardial infarction (MI) is a main cause of morbidity and mortality worldwide. Due to insufficient blood supply (ischemia) parts of the myocardium will die by uncontrolled cell death, necrosis. Restoration of blood supply will reoxygenize the tissue, although this will paradoxically also increase myocardial necrosis (reperfusion injury). During necrosis, intracellular components are released into the extracellular environment and are potent triggers of sterile inflammation through activation of the innate immune system. Such triggers are termed damage associated molecular patterns (DAMPs). Mitochondria are evolutionary endosymbionts from bacteria and share similarities with bacterial immunogens upon infection. Thirty per cent of cardiomyocyte volume is mitochondria. Consequently, a high concentration of mitochondrial DAMPs are released upon myocardial necrosis. We hypothesized that controlling the local sterile inflammatory response will reduce cardiac damage after MI and thereby reduce the risk of developing heart failure. In the present thesis we have investigated different aspect of innate immune activation in the heart and in cardiac cells. We have shown that nucleolin binds extracellular DNA, including mitochondrial DNA. Blocking nucleolin reduced uptake of immunogenic DNA and reduced inflammatory responses in cardiomyocytes exposed to hypoxia/reoxygenation. Inhibiting the innate immune receptor Toll-like receptor 4 at reperfusion reduced infarct size and interleukin-6 release, possibly exacerbated by mitochondrial DAMPs. We have also excluded a direct effect of mitochondrial N-formyl peptides in cardiomyocytes, as they do not express the formyl peptide receptors. Furthermore, we have shown that proteasomal degradation is the major catabolic anti-inflammatory mechanism for degradation of pro-IL-1β in cardiac fibroblasts. Lastly, we showed that intracellular C3 is expressed in cardiomyocytes and cardiac fibroblasts, and protects the heart against ischemia-reperfusion. As MI induce a large sterile inflammation, targeting the innate immune system may be a potential target for treating cardiac ischemia-reperfusion injury.
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