Abdominal aortic aneurysms (AAA) occur commonly in the elderly population and are a major cause of morbidity and mortality. The mechanisms responsible for aneurysm formation are poorly understood, which has impeded identification of effective medical therapies for this disease. Mounting evidence from studies in human AAA, and in experimental animal models, suggests that oxidative stress plays a key role in the pathogenesis of AAA. While a number of enzymatic pathways are capable of inducing vascular oxidant stress and potentially contributing to AAA, we hypothesis that myeloperoxidase (MPO) is instrumental in this process. MPO is an enzyme expressed primarily in neutrophils (PMNs) and to a lesser extent in monocytes/macrophages, that catalyzes the formation of HOCl, a powerful oxidizing specie, and induces protein nitration. In addition, MPO can be taken up into the blood vessel wall, thus amplifying inflammation, oxidative stress and protease degradation. Using two distinct murine models (elastase-induced and angiotensin II infusion in hyperlipidemic mice), we present data showing that aortic MPO activity and chlorotyrosine expression (a marker of HOCl-mediated oxidative stress) are increased during experimental AAA formation. Our data also suggest a potentially novel role for angiotensin II to exacerbate HOCl-mediated oxidative stress in the blood vessel wall. Moreover, supplementation with taurine, a beta amino acid that reacts with and detoxifies HOCl, prevents AAA formation in these experimental models. To test our hypothesis, we propose three specific aims.
In aim 1, we will perform selective immunodepletion and adoptive transfer of PMNs from control or MPO- deficient mice.to test the hypothesis that MPO expression in PMNs contributes to experimental AAA formation in the elastase model. Also, we will immnuodeplete PMNs to determine their role in AAA formation in the angiotensin II infusion model.
In aim 2, we will test the hypothesis that genetic deficiency of MPO ameliorates AAA formation in the elastase-induced and angiotensin II infusion models.
In aim 3, we will test the hypothesis that transgenic expression of human MPO augments experimental AAA formation.
In aims 2 and 3, we will also determine whether angiotensin II upregulates expression and activity of MPO in leukocytes, and whether MPO modulates hypertension and atherosclerosis induced by angiotensin II infusion. Our studies will provide novel insight into mechanisms of AAA formation and linkages between key oxidant stress generating pathways in the pathogenesis of cardiovascular disease.

Public Health Relevance

Abdominal aortic aneurysms are common in elderly Americans and can lead to progressive enlargement and even rupture of the aorta, the largest blood vessel in the body. Our research suggests that an enzyme known as myeloperoxidase, which is present in white blood cells, contributes to inflammation and tissue damage within the aorta, leading to aneurysm formation. The purpose of our research is to investigate the role of myeloperoxidase in aneurysm formation in experimental animal models, and then to determine whether countermeasures against myeloperoxidase may be effective in treating aneurysms in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076684-07
Application #
8215740
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (02))
Program Officer
Goldberg, Suzanne H
Project Start
2004-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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