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- Ocaya, Pauline, 1980-
(författare)
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Retinoid metabolism and signalling in vascular smooth muscle cells
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Smooth muscle cells (SMCs) play a major role in cardiovascular diseases. In advanced atherosclerosis, blood flow is impaired due to reduced luminal diameter. Percutaneous vascular interventions, including balloon angioplasty and stent-application are commonly used for the re-establishment of luminal size and improvement of tissue perfusion. However, the benefit of vascular interventions is hampered by re-stenosis. The molecular basis of re-stenosis is not fully elucidated and so far, no successful treatment is clinically available. Re-stenosis, which is proposed to be a response to mechanical injury, involves the activation of multiple processes including inflammation, SMC migration and proliferation, and is characterized by vessel remodelling and intimal hyperplasia. Retinoids have been shown to regulate several processes activated at site of vascular injury including inflammation, SMC migration and proliferation, and have been demonstrated to inhibit SMC proliferation and reduce intimal hyperplasia. Thus, retinoids are potential candidates in the treatment of certain vascular disorders. Retinoid metabolism is complex and involves a repertoire of proteins including retinoic acid synthesizing and catabolizing enzymes. The purpose of this study was to investigate retinoid metabolism in vascular cells, more specifically to find key points in the regulation of retinoid metabolism in vascular SMCs and atherosclerotic lesions. We demonstrate that different phenotypes of SMCs exhibit differences in retinoid metabolism, which suggests a link between retinoid metabolism and the SMC phenotype. Vascular SMCs and atherosclerotic lesions expressed cytochrome P450 isoform 26 (CYP26) enzymes, which are involved in retinoid catabolism. Our studies reveal the presence of a negative feedback loop, in which retinoids induce its inactivation by inducing CYP26 expression in vascular SMCs and atherosclerotic lesions. Moreover, inhibition of CYP26 potently blocked retinoid catabolism and resulted in retinoid-like effects in SMCs, indicating that CYP26 is an important endogenous modulator of retinoid metabolism in vascular cells. In atherosclerotic lesions and vascular SMCs, decreased retinoid catabolism and hence, increased retinoid availability, resulted in increased expression of retinoid-responsive genes. Since retinoids reduce intimal hyperplasia in animal models, our studies suggest that CYP26 inhibitors may provide an alternative to exogenous retinoid administration. Thus, CYP26 inhibitors may offer a new therapeutic approach to vascular proliferative disorders.
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| 2. |
- 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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