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- Jatta, Ken
(författare)
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Inflammation in atherosclerosis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Consequences of atherosclerosis may result in a number of diseases of the cardiovascular system that represent serious health problems and major causes of morbidity and mortality worldwide. Although it is initially considered as disease of fibro-lipid and thrombus deposition in the arterial wall, it also involves an ongoing inflammatory response. Normally, the inflammatory response is considered as a protective defence mechanism of the body. However, if the inflammation gets out of proportion to the threat it is dealing with, it may then result in a sustained chronic disorder and thus may underlie the initial stage of atherogenesis. The work of this thesis focuses on the expression of cytokines/chemokines and the vascular transcriptional response to inflammation, i.e. LPS in atherosclerosis. This has mainly been studied in animal models of atherosclerosis; consequently, we set out to investigate these events using human material in vitro (human carotid lesions). Employing quantitative analysis, we were able to detect a significant induction of protein and mRNA of the cytokines IL-1β, IL-6, IL-10 and TNF-α and the chemokines IL-8 and MCP-1 by LPS in both atherosclerotic and non-atherosclerotic vessels. In contrast, LPS induction of TNF-α, IL-1β and IL-10 was solely observed in the lesions, but not in normal arteries. In addition, the impact of IL-1 gene polymorphism on the risk of myocardial infarction (MI) was estimated by DNA genotyping of 387 survivors of a first MI and 387 sex and age-matched control subjects. We found no statistically significant differences in either genotypic distribution or allelic frequencies of IL-1β (-511) or IL-1Ra (VNTR) polymorphisms between first-time survivors of myocardial infarction and their age-matched healthy controls. Incontrast, our results demonstrated a strong association between the IL-1Ra genotype and severity of angiographically determined coronary artery disease in post-MI patients. To further investigate the vascular response to inflammation, we used gene array analysis to evaluate the human vascular transcriptional response to LPS of non-atherosclerotic human renal arteries compared to carotid lesions. In LPS treated renal arteries, 54% of the transcripts gave a detectable signal, where 4% were upregulated and 3.8% down-regulated. In the LPS stimulated carotid lesions, 44% of transcripts were detected. In this latter group, 5.1% of transcripts were increased and 3.3% decreased. Interestingly, a newly identified virus-inducible antiviral protein, CMV inducible gene 5/viperin (Cig5), was among the most strongly induced gene in both normal and atherosclerotic biopsies. Single gene analysis revealed viperin in the endothelium of human atherosclerotic lesions. Further, viperin was induced in vascular cells by inflammatory stimuli and CMV infection. In conclusion we show that atherosclerotic vessels produce more proinflammatory cytokines/chemokines than normal vessels. Interestingly, our results indicate that LPS enhances the expression of cytokines/chemokines in a similar pattern both in lesions and normal arteries. However, the response is stronger in atherosclerotic lesions. Furthermore, our results suggest that genetic polymorphisms within the IL-1Ra loci may influence the severity of CAD. Finally, the CMV inducible gene 5/viperin have been identified as a putative culprit molecule in vascular inflammation and atherosclerosis.
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| 2. |
- Zegeye, Mulugeta Melkie, 1986-
(författare)
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Interleukin-6 Signaling Pathways in Human Vascular Endothelial Cells : Molecular Mechanisms and Associations to Atherosclerosis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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