Weakening and dilation of the main abdominal artery (aortic aneurysm, AAA) affects 5-10% of men and 1% of women aged over 60 years. The weakening process is usually progressive and without surgical repair the artery can burst usually leading to death. Despite improved medical treatment of artery disease the incidence of this problem is increasing. At present no medication has been clearly shown to halt or slow the artery weakening in humans. The aortic weakening results from inflammation, protein degrading enzymes and loss of vascular smooth muscle cells (VSMC). In this study we investigate the role of two calcium-controlling proteins, osteoprotegerin (OPG) and osteopontin (OPN), in human artery weakening. These proteins are of particular interest because preliminary human, animal and cell studies suggest they may be of critical importance in AAA. The role of OPG and OPN in AAA development and progression will be assessed by a combination of human, animal and cell culture experiments. The effect of variation in the OPG and OPN genes on AAA development and progression will be assessed by genetic analysis of DNA from 4045 participants in the Western Australian AAA study. The influence of OPG and OPN on inflammation, protein degrading enzymes and VSMC loss will be studied in cell culture and an animal model of AAA. Finally, two potential medical treatments for AAA will be assessed as to their effect on OPG and OPN utilizing cell culture and animal studies. Understanding the role of these calcium-controlling proteins in artery weakness and how drug therapy can interfere in these effects is an important step in the development of new treatment for aortic aneurysm. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080010-03
Application #
7236088
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wassef, Momtaz K
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$256,009
Indirect Cost
Name
James Cook University of No Queensland
Department
Type
DUNS #
758372957
City
Townsville
State
Country
Australia
Zip Code
4817
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Subramanian, Venkateswaran; Golledge, Jonathan; Heywood, Elizabeth B et al. (2012) Regulation of peroxisome proliferator-activated receptor-? by angiotensin II via transforming growth factor-?1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 32:397-405
Pal, Shripad N; Clancy, Paula; Golledge, Jonathan (2011) Circulating concentrations of stem-cell-mobilizing cytokines are associated with levels of osteoprogenitor cells and aortic calcification severity. Circ J 75:1227-34
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Golledge, Jonathan; Biros, Erik; Warrington, Nicole et al. (2011) A population-based study of polymorphisms in genes related to sex hormones and abdominal aortic aneurysm. Eur J Hum Genet 19:363-6
Parr, Adam; McCann, Moira; Bradshaw, Barbara et al. (2011) Thrombus volume is associated with cardiovascular events and aneurysm growth in patients who have abdominal aortic aneurysms. J Vasc Surg 53:28-35
Trollope, Alexandra F; Golledge, Jonathan (2011) Angiopoietins, abdominal aortic aneurysm and atherosclerosis. Atherosclerosis 214:237-43
Pal, Shripad N; Rush, Catherine; Parr, Adam et al. (2010) Osteocalcin positive mononuclear cells are associated with the severity of aortic calcification. Atherosclerosis 210:88-93
Ferguson, Craig D; Clancy, Paula; Bourke, Bernard et al. (2010) Association of statin prescription with small abdominal aortic aneurysm progression. Am Heart J 159:307-13
Golledge, Jonathan; Cullen, Bradford; Rush, Catherine et al. (2010) Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis 210:51-6

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