Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Rob Storey, University of Sheffield, UK,
- Second opponent: Professor Stefan James, Uppsala University Hospital, Sweden,
- Third member and chair of the evaluation committee: Professor II Theresa Olasveengen, University of Oslo
Chair of the Defence
Professor Mathis Korseberg Stokke, University of Oslo
Principal Supervisor
Professor emeritus Ingebjørg Seljeflot, University of Oslo
Summary
Despite advances in treatment of coronary artery disease (CAD) the last decades, with percutaneous coronary intervention (PCI) and improved medication, CAD is still a leading cause of death, and search for new therapeutic targets is ongoing. There is a vast number of different cytokines, receptors, enzymes and other molecules implicated in the atherosclerotic process, thrombus formation, acute myocardial infarction (AMI) and ischemia-reperfusion injury after revascularization in an AMI.
The overall aim of this thesis was to get further knowledge on the molecular mechanisms involved in AMI with thrombus formation. Relationships between molecules of action, cell types involved, infarct size and time from symptom onset to reperfusion were explored in detail. Presence, localization and genetic expression of inflammasome- and Interleukin (IL)-6 signaling-related proteins, metalloproteinases and fibrinolytic markers were studied in coronary thrombi aspirated from patients with ST-elevation myocardial infarction (STEMI). Any associations between circulating microvesicles (MVs) and inflammasome- and IL-6 signaling were also explored.
The studied markers were all found present and genetically expressed in the coronary thrombi. Expression of TLR4, NLRP3, IL-6R, gp130 and TIMP-1 in thrombi associated significantly with myocardial injury assessed by troponin T, as did the expression of TLR4, NLRP3 and TIMP-1 in circulating leukocytes. They were all closely connected with monocytes/macrophages in the thrombi. None of the investigated genes in thrombi associated with corresponding circulating levels, or with time from symptoms to PCI. It was demonstrated that a subgroup of MVs associated with expression of NLRP3 in the thrombi.
The findings support continuing targeting the Inflammasome pathway, and suggest moving upstream in the cascade, in the search for treatment to reduce residual inflammatory burden in AMI, and also points to TIMP-1 as a possible target in cardiac remodeling.
Additional information
Contact the research support staff.