Role of angiotensin II and inflammatory cells in the development of human abdominal aortic aneurysm

Fang Hua (2005). Role of angiotensin II and inflammatory cells in the development of human abdominal aortic aneurysm PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Fang Hua
Thesis Title Role of angiotensin II and inflammatory cells in the development of human abdominal aortic aneurysm
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor Prof Malcolm West
Dr. Maria Nataatmadja
Dr. Fraser Russell
Total pages 148
Language eng
Subjects 11 Medical and Health Sciences
L
Formatted abstract

Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease affecting aged people. Chronic inflammation and enzymatic degradation of elastic lamellae and extracellular matrix (ECM) proteins constitute the most prominent pathological characteristics of AAA. Increased levels of matrix metalloproteinase (MMP) expression and activity have been demonstrated within the aortic wall of AAA and many cell types in the aneurysmal wall can express MMP including inflammatory cells, smooth muscle cells and fibroblasts. However, the reason why MMP expression is increased in AAA is largely unknown. Angiotensin II (Ang II) is a circulating peptide regulating blood pressure as well as a pro-inflammatory and proliferative autocrine factor and may therefore contribute to the development of AAA. This thesis will investigate possible roles of Ang II in the regulation of MMP in aortic cells in the pathogenesis of AAA. 

In this study, fresh aortas were obtained from AAA patients during reparative surgery or from multiple organ donors. Tissues were processed for general histopathology or immunohistology. Histopathological examination of AAA showed loss of vascular smooth muscle cells, extracellular matrix degradation, adventitial fibrosis and infiltration of inflammatory cells including mast cells, macrophages and lymphocytes into the diseased wall. As mast cells can secrete chymase, the main Ang II forming enzyme in human aorta, the cellular distribution and quantitation of mast cells were particularly investigated. Increased mast cell numbers were found in the aneurysmal wall compared with control aorta. Quantitation of mast cells in each tunica revealed that increased mast cell number in the adventitia of AAA is responsible for the total increase of mast cell numbers compared with control. Furthermore, activated mast cells are also increased in AAA compared with control. This indicates that tissue AngII formation may be elevated in AAA. Ang II receptor expression in control and AAA was then investigated. In AAA, Ang II type I and type II receptors were expressed in infiltrating inflammatory cells while in control aorta they were expressed largely in VSMCs indicating a complete different distribution pattern. Furthermore, increased expression of AT1 receptors was also found in adventitial fibroblasts in AAA compared with control. It suggests that vascular fibroblasts and inflammatory cells might be stimulated by Ang II and play an important role in AAA development. In order to further investigate the mechanism of cell response and cell-to-cell interactions in vitro, cell culture and co-culture were carried out. MMP expression and activity were measured by Western blot and zymography respectively. Ang II receptor expression was also measured by Western blot. Data were quantitated and presented as mean ± SEM. 

Cultured fibroblasts were stimulated by Ang II for 2, 3 or 4 days and then cell number and MMP expression were determined. Cell proliferation was found after 96 hours but this was inhibited by AT1 receptor. However, Ang II stimulation did not increase MMP expression or activity of fibroblasts suggesting that Ang II may not directly regulate MMP expression of fibroblasts but may contribute to AAA fibrosis. Because AT1 and AT2 receptors were expressed in AAA and increased MMP expression was found co-localised with inflammatory cells such as macrophages and lymphocytes, a co-culture study of monocytes and fibroblasts were carried out. Human CD 14+ monocytes were stimulated by Ang II and co-cultured with vascular fibroblasts or smooth muscle cells. After co-incubation for 4 days, co-cultured fibroblasts, but not smooth muscle cells, showed increased secretion of pro- and active MMP-2. These surprising findings suggest that an interaction between monocytes and fibroblasts involving release of inflammatory cell-derived factors might exist to upregulate MMP expression of fibroblasts. 

This study implicated Ang II as a pathogenetic factor affecting multiple cell types, especially inflammatory cells and fibroblasts. It suggests that Ang II might regulate MMP expression in the aortic wall via inflammatory cells therefore contributing to development of AAA. As a result, inhibition of Ang II might be a beneficial target for the clinical treatment of AAA. 

Keyword Angiotensin II
Aortic aneurysms
Abdominal aneurysm
Additional Notes

Variant title: Angiotensin II and inflammatory cells in aneurysm

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
 
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Created: Wed, 13 Jun 2012, 16:18:47 EST by Erica Wei on behalf of Scholarly Communication and Digitisation Service