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- Befekadu Wodajo, Rahel, 1968-
(author)
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Analysis of new biomarkers and their kinetics in connection with ST-elevation myocardial infarction and percutaneous coronary intervention
- 2022
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Doctoral thesis (other academic/artistic)abstract
- This thesis studies different biomarkers in a cohort of patients suffering from ST-elevation myocardial infarction (STEMI) who underwent Percutaneous coronary intervention (PCI) in Örebro in 2011-2012. Blood samples were collected at three time points, at the arrival at the hospital, 1-3 days after PCI and for a smaller group of patients also 3 months after PCI. The study is a sub-study of the TASTE study, so half of the patients were also randomized to thrombus aspiration in conjunction with their PCI. For all patients, it was also recorded whether the culprit coronary vessel was totally occluded or partially patent. In total, there are samples from 165 patients, but not all markers have been measured in all patients, and 3-month samples are only available from those who had their follow-up in Örebro. The plasma levels of the biomarkers have also been measured in plasma from blood donors for comparison. In March 2019, a follow-up was made of the patients' survival, and the time of death was noted in cases where this had occurred.The markers studied are the lysosome protein Cathepsin S (Cat-S), the platelet granule protein thrombospondin 1 (TSP-1), the pentraxins C-reactive protein (CRP) and pentraxin 3 (PTX3), the endopeptidase neprilysin, the soluble forms of TNF-receptor 1 and 2 (sTNFR1 and sTNFR2), markers showing activation of the lectin pathway for complement activation (MASP-1/AT, MASP-1/C1-INH, MASP-2/C1-INH, MASP-2/AT) and common activation markers for complement activation (C3a and sC5b-9).In summary, the thesis shows that the plasma levels of all markers, except neprilysin and sC5b-9, are elevated at the time of arrival compared to healthy blood donors. Neprilysin is at the same level, and sC5b-9 is lower compared to blood donors. 1-3 days after PCI, the levels for CRP, sTNFR1 and sC5b-9 have risen strongly (>50%) compared to the levels at arrival. MASP-1/AT and MASP-2/AT have fallen moderately (about 50%), Cat-S and TSP-1 have decreased strongly, while the remaining markers are relatively similar to the levels at arrival (± 25%). The levels for CRP, PTX3, sTNFR1, sTNFR2 and neprilysin decreased even further between 1-3 days and 3 months, sC5b-9 rises slightly while the other markers remain at roughly the same levels. At 3 months, most markers still show higher levels compared to corresponding levels in blood donors, only MASP-2/C1-INH has the same level, while neprilysin is slightly lower and TSP-1 much lower compared to blood donors (the latter presumably an effect of ongoing medication with platelet inhibitors in the patients). No relevant differences were observed between patients with and without thrombus aspiration, and few differences were seen between patients with occluded or partially patent vessels. This may indicate that these factors were of minor importance for the levels of the analyzed markers. In contrast, analysis of survival showed that individuals with plasma levels above the median value for PTX3, sTNFR1 and sTNFR2 at admission and/or at 1-3 days had a significantly increased mortality compared to those with levels below the median value, which indicates that these markers could be interesting for further studies in a material where also analysis of possible interfering factors can be implemented.
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- Zegeye, Mulugeta Melkie, 1986-
(author)
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Interleukin-6 Signaling Pathways in Human Vascular Endothelial Cells : Molecular Mechanisms and Associations to Atherosclerosis
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Interleukin-6 is pleotropic cytokine produced by several types of cells including endothelial cells (ECs). IL-6 acts on target cells via two major signaling mechanisms known as classic signaling and trans-signaling. Whileactivation of IL-6 classic signaling is associated with homeostatic and tissue regeneration functions, the trans-signaling is linked to pro-inflammatory effects. Our studies reveal that ECs respond to both IL-6 classic- aswell as trans-singling pathways in distinct but also overlapping manner.While IL-6 classic-signaling activated JAK/STAT3 pathway, the trans-signaling additionally engaged PI3K/AKT and MAPK/ERK pathways. Further, IL-6 trans-singling, but not classic signaling, led to secretion of proinflammatory chemokine MCP-1 mainly via JAK/STAT3 and PI3K/AKTpathways. In addition, IL-6 trans-signaling regulate expression of angiogenesis related genes to subsequently impair endothelial tube formationability. Autocrine IL-6 classic-signaling, however, was vital to maintainthe angiogenic response of ECs. Further proteomic analyses showed thatIL-6 trans-signaling in ECs regulates secretion of several inflammatoryproteins and also shifts laminin secretion from LAMA4 to LAMA5, whichmight collectively favor binding and trans-endothelial migration of mononuclear cells. In human atherosclerotic plaques, we found that expression of LAMA4 and LAMA5 is altered compared to healthy vessels, andthat the alteration appears to be associated with immune cell content andstability of the plaque. Using plasma IL-6 binary complex, a novel biomarker, we showed a strong association between IL-6 trans-signalingand risk of future myocardial infarction (MI). In addition, we showed thatelevated plasma IL-6 binary complex mediates the association betweentraditional risk factors (hypertension and smoking) and MI, suggestingthat elevated plasma IL-6 binary complex concentration could partly explain the increased risk of MI in smokers and hypertensive participants.
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| 3. |
- Kardeby, Caroline, 1989-
(author)
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Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.
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| 4. |
- Lindkvist, Madelene, 1984-
(author)
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Impact of Interleukin-6 family cytokine signalling on human endothelial cells and platelets
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Endothelial cells lining the luminal side of blood vessels creates a barrier between the circulating blood and the extracellular matrix. Endothelial cells have important functions in regulation of vessel tension and inflammation. Furthermore, endothelium-derived vasodilators prevent our smallest blood cells, platelets, to aggregate in the circulation. The main physiological role of platelets is to protect us from bleeding by creating aggregates at sites of injury. Platelets is also increasingly recognised as mediators in acute inflammation. The focus of this thesis has been to study the impact of inflammatory cytokines in the interleukin (IL)-6 family on endothelial cells and platelets. IL-6 has pleiotropic effects where IL-6 trans-signalling via the soluble IL-6 receptor (IL-6R) is associated to more pro-inflammatory outcomes than classic signalling via the membrane bound IL-6R. Both classic and trans-signalling need the ubiquitously expressed glycoprotein (gp)130 to induce intracellular signalling. Since the IL-6R is expressed on a restricted number of cell types, transsignalling exerts a broader IL-6 response. Paper I reveal that endothelial cells express IL-6R which facilitates both classic and trans-signalling. IL-6 trans-signalling activates more signalling pathways and results in proinflammatory responses in contrast to classic signalling. Paper II show that IL-6 trans-signalling, but not classic signalling occurs in platelets and results in inhibition of epinephrine-induced platelet aggregation. Paper III reveal inter-individual differences in platelet reactivity towards activators and the inhibitor nitric oxide (NO). Individuals with more NOsensitive platelets showed greater capacity of vasodilation, indicating a connection between endothelial function and platelet inhibition. In Paper IV, the impact of various gp130 signalling cytokines on endothelial cells revealed differences and similarities in intracellular signalling, gene expression and protein release. In summary, this thesis investigates the impact of the IL-6 family cytokines on endothelial cells and platelets in regards of intracellular signalling and functional responses.
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