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Semicarbazide-sensitive amine oxidase and vascular complications in diabetes mellitus: Biochemical and molecular aspects
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Pharmacology.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs).

This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 51
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1174
Keywords [en]
Pharmacology, diabetes, SSAO, VAP-1, retinopathy, methylamine, aminoacetone, hydralazine
Keywords [sv]
Farmakologi
National Category
Pharmacology and Toxicology
Research subject
Medical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-2566ISBN: 91-554-5375-9 (print)OAI: oai:DiVA.org:uu-2566DiVA, id: diva2:161901
Public defence
2002-10-11, lecture room B21, Biomedical Center (BMC), Uppsala, 13:15
Opponent
Available from: 2002-09-19 Created: 2002-09-19 Last updated: 2018-01-13Bibliographically approved

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