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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (02))
Program Officer
Tolunay, Eser
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Zhang, Lan; Pan, Yaohua; Qin, Gangjian et al. (2014) Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: improving the safety of iPS cell transplantation to myocardium. Cell Cycle 13:762-71
Manka, David; Chatterjee, Tapan K; Stoll, Lynn L et al. (2014) Transplanted perivascular adipose tissue accelerates injury-induced neointimal hyperplasia: role of monocyte chemoattractant protein-1. Arterioscler Thromb Vasc Biol 34:1723-30
Omar, Abdullah; Chatterjee, Tapan K; Tang, Yaoliang et al. (2014) Proinflammatory phenotype of perivascular adipocytes. Arterioscler Thromb Vasc Biol 34:1631-6
Chatterjee, Tapan K; Basford, Joshua E; Knoll, Ellen et al. (2014) HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes 63:176-87
Chen, Lijuan; Phillips, M Ian; Miao, Hui-Lai et al. (2014) Infrared fluorescent protein 1.4 genetic labeling tracks engrafted cardiac progenitor cells in mouse ischemic hearts. PLoS One 9:e107841
Zhang, Lan; Zhou, Mi; Qin, Gangjian et al. (2014) MiR-92a regulates viability and angiogenesis of endothelial cells under oxidative stress. Biochem Biophys Res Commun 446:952-8
Wang, Yingjie; Zhou, Mi; Wang, Xiaolong et al. (2014) Assessing in vitro stem-cell function and tracking engraftment of stem cells in ischaemic hearts by using novel iRFP gene labelling. J Cell Mol Med 18:1889-94
Ranganathan, Punithavathi; Jayakumar, Calpurnia; Mohamed, Riyaz et al. (2014) Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury. Am J Physiol Renal Physiol 307:F183-94
Zhang, Lan; Zhou, Mi; Wang, Yingjie et al. (2014) miR-92a inhibits vascular smooth muscle cell apoptosis: role of the MKK4-JNK pathway. Apoptosis 19:975-83
Wang, Yingjie; Zhang, Lan; Pan, Yaohua et al. (2013) Identification of stem cells after transplantation. Methods Mol Biol 1036:89-94

Showing the most recent 10 out of 36 publications