Urocortin 2: an interesting role in human abdominal aortic aneurysm

Emeto, Theophilus Ikenna (2013) Urocortin 2: an interesting role in human abdominal aortic aneurysm. PhD thesis, James Cook University.

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Abstract

Acquired cardiovascular diseases such as coronary heart disease, peripheral artery disease, abdominal aortic aneurysm (AAA) and related vascular problems contribute to more than one-third of worldwide morbidity and mortality. In many instances, particularly in the under developed world, cardiovascular diseases are diagnosed at a late stage limiting the scope for improving outcomes. AAA accounts for thousands of deaths in the western world including Australia annually. It is estimated to be the tenth leading cause of death in those aged over 60 years. Hundreds of millions of dollars are spent annually to treat and manage AAA in Australia. Current methods of diagnosing and managing AAA are expensive and not very efficient, necessitating research into identifying blood borne markers involved in AAA pathology that could offer a cheap diagnostic and/or prognostic alternative, or serve as a therapeutic target for disease management.

The urocortins (UCNs) are a group of recently defined protein members of the corticotrophin–releasing factor family. Previous pre-clinical work and human association studies suggest that UCNs have potential to exert either beneficial or detrimental effects on the heart and major blood vessels. Current evidence favours beneficial effects of UCNs within the cardiovascular system, for example, these proteins have been shown to inhibit production of reactive oxygen species and apoptosis, implying a potential to antagonise the progression of cardiovascular disease.

Loss of medial smooth muscle cells is believed to be a critical feature of AAA. The UCNs have been previously reported to regulate the proliferation and survival of various cell types. Urocortin 2 (UCN2) particularly was reported to inhibit the proliferation and survival of Lewis lung carcinoma cells. The objective of the work discussed in this thesis was to elucidate the expression and functional role of UCNs in human AAA development and progression both in vivo and in vitro.

To this end, urocortin 3 (UCN3) was demonstrated to play no role in aneurysm development in a mouse model of AAA. More importantly, UCN2 and its receptor, corticotrophin releasing factor receptor 2 (CRFR2), were shown to be significantly over expressed in biopsies taken from the main dilated region of human AAAs compared to non-aneurysmal aortic tissues. Plasma concentrations of UCN2 were demonstrated to be significantly higher in patients with AAA compared to patients with non-aneurysmal peripheral artery disease even after adjusting for confounding cardiovascular risk factors. In vitro, UCN2 was shown to promote AAA pathogenesis by stimulating an aneurysmal phenotype on human aortic smooth muscles cells (HASMC); an effect that was significantly abrogated by Astressin-2B the selective CRFR2 antagonist. The work described in this thesis demonstrated for the first time an association between UCN2 and AAA in man. This effect may be restricted to UCN2 alone, but it is unlikely given that other analogues of the peptide-urocortin1 (UCN1) and UCN3 have been found in the disease environment. It is proposed that UCN2 may serve as a possible therapeutic target in AAA, although further work is required to validate these findings.

Item ID: 29838
Item Type: Thesis (PhD)
Keywords: acquired cardiovascular diseases; urocortins; abdominal aortic aneurysm; preventative medicine
Additional Information:

Appendix 1 (administrative documentation) is not available through this repository.

Publications arising from this thesis are available from the Related URLs field. The publications are:

Emeto, Theophilus I., Moxon, Joseph V., Rush, Catherine, Woodward, Lynn, and Golledge, Jonathan (2011) Relevance of urocortins to cardiovascular disease. Journal of Molecular and Cellular Cardiology, 51 (3). pp. 299-307.

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Date Deposited: 18 Oct 2013 05:16
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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