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Semicarbazide-sensitive Amine Oxidase (SSAO) – Regulation and Involvement in Blood Vessel Damage with Special Regard to Diabetes: A Study on Mice Overexpressing Human SSAO
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6) belongs to a family of copper-containing amine oxidases. SSAO exists as a membrane bound protein in endothelial-, smooth muscle-, and adipose cells as well as soluble in plasma. SSAO catalyses oxidative deamination of primary monoamines, which results in the production of corresponding aldehydes, hydrogen peroxide and ammonia. These compounds are very reactive and potentially cytotoxic, and are able to induce vascular damage if produced in high levels. Patients with diabetes mellitus, and with diabetic complications in particular, have a higher SSAO activity in plasma compared to healthy controls. It has therefore been speculated that high SSAO activity is involved in the development of vascular complications associated with diabetes. The aim of this thesis is to investigate the importance of SSAO in the development of disorders of a vascular origin. We have studied the transcriptional regulation of the SSAO gene, by inducing diabetes in NMRI and in transgenic mice, overexpressing the human form of SSAO in smooth muscle cells. We found that the increase in SSAO activity in diabetes is accompanied by reduced mRNA levels of the endogenous mouse gene, suggesting a negative feedback on the transcription of the SSAO gene. In addition, the transgenic mice exhibited an abnormal phenotype in the elastic tissue of aorta and renal artery. These mice have a lower mean artery pressure and an elevated pulse pressure. These results indicate that high SSAO activity in smooth muscle cells is associated with a change in the morphology of large arteries. This is likely contributing to the development of vascular complications in diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 54
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1391
Keywords [en]
Pharmacology, amine oxidases, VAP-1, vascular complications, diabetes, blood pressure
Keywords [sv]
Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-4673ISBN: 91-554-6098-4 (print)OAI: oai:DiVA.org:uu-4673DiVA, id: diva2:165456
Public defence
2004-12-10, Room B41, Building A4, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Semicarbazide-sensitive amine oxidase (SSAO gene expression in alloxan-induced diabetes in mice
Open this publication in new window or tab >>Semicarbazide-sensitive amine oxidase (SSAO gene expression in alloxan-induced diabetes in mice
2002 In: Molecular Medicin, ISSN 1076-1551, Vol. 8, no 12, p. 824-829Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92396 (URN)
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved
2. Overexpression of semicarbazide-sensitive amine oxidase in smooth muscle cells leads to an abnormal structure of the aortic elastic laminas
Open this publication in new window or tab >>Overexpression of semicarbazide-sensitive amine oxidase in smooth muscle cells leads to an abnormal structure of the aortic elastic laminas
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2003 In: American Journal of Pathology, ISSN 0002-9440, Vol. 163, no 5, p. 1921-1928Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92397 (URN)
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved
3. Semicarbazide-sensitive amine oxidase in transgenic mice with diabetes
Open this publication in new window or tab >>Semicarbazide-sensitive amine oxidase in transgenic mice with diabetes
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2004 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 325, no 3, p. 1013-1020Article in journal (Refereed) Published
Abstract [en]

Semicarbazide-sensitive amine oxidase (SSAO) activity in plasma is increased in diabetes, and in particular, in diabetic patients with vascular complications. It has been speculated that SSAO is involved in the development of such complications due to the production of cytotoxic compounds. In this work, we have induced diabetes in a previously described mouse-model, overexpressing SSAO in smooth muscle cells. SSAO activity was estimated as well as expression of the endogenous mouse gene and human transgene using real-time PCR. Diabetes induced an increase in SSAO activity in serum, kidney, and adipose tissue of transgenic animals. An inverse correlation between SSAO activity and mouse SSAO mRNA levels was observed in transgenic animals with diabetes. These results further support the suggestion of a negative feedback control of the SSAO gene expression. The increased SSAO activity in diabetes is most likely dependent on post-transcriptional modifications or activation of existing inactive enzyme molecules.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92398 (URN)10.1016/j.bbrc.2004.10.140 (DOI)15541390 (PubMedID)
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2018-05-31Bibliographically approved
4. Transgenic mice overexpressing Semicarbazide-sensitive amine oxidase (SSAO) have an elevated pulse pressure
Open this publication in new window or tab >>Transgenic mice overexpressing Semicarbazide-sensitive amine oxidase (SSAO) have an elevated pulse pressure
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92399 (URN)
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2010-01-13Bibliographically approved

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