The overall goals of this continuing Program Project are to develop a better understanding of the mechanisms linking oxidation and inflammation to cardiovascular disease. Each project focuses on elucidating mechanisms of how distinct yet interconnecting pathways of oxidation operative during inflammation contribute to cardiovascular disease and disrupt homeostatic mechanisms normally responsible for resolution of inflammatory responses. The Program Project is led by a team of highly productive experts and comprised of 3 interrelated projects and 4 cores. Project 1 focuses on the leukocyte-derived heme protein myeloperoxidase (MPO), an enzyme that can catalytically consume nitric oxide and is a critical participant in oxidative and inflammatory injury during atherosclerosis. Genetic, biophysical and clinical studies are proposed to further define mechanisms responsible for regulating MPO activity in vivo and their links to development of cardiovascular disease. Project 2 is thematically linked to Projects 1 and 3, and explores both the role of the ribosomai protein L13a in post transcriptional resolution of inflammatory gene expression, and the inhibition in this inflammation response """"""""off switch"""""""" by the actions of myeloperoxidaseand nitric oxide-derived oxidants. The theme of inflammation and oxidation continues in Project 3, which will study mechanisms through which endothelial nitric oxide synthase becomes """"""""uncoupled"""""""", leading to increased oxidant production, endothelial dysfunction and cardiovascular disease. Three scientific cores (Mass Spectrometry;Biophysical and Computational Chemistry;and Protein Engineering and Expression) and an Administrative Core provide multiproject support, expertise and service in a cost-effective manner, significantly strengthening the entire research program. The Program Project also benefits from shared access to a large repository of clinical samples and connecting database from well-characterized patients who underwent elective cardiac catheterization and for whom long-term follow-up is available. The proposed Program Project will yield a greater understanding of the role of oxidation in normal physiologic processes and disease pathogenesis. It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy.

Public Health Relevance

The overall goal of this Program Project is to develop a better understanding of the mechanisms linking oxidation and inflammation to cardiovascular disease. Special emphasis is placed on studies of specific enzymes found in white blood cells and cells of the artery wall involved in nitric oxide synthesis, their role in causing vascular injury, as well as mechanisms for inhibiting resolution of vascular inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL076491-08
Application #
8217166
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed AK
Project Start
2004-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$1,832,428
Indirect Cost
$628,912
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Wang, Zeneng; DiDonato, Joseph A; Buffa, Jennifer et al. (2016) Eosinophil Peroxidase Catalyzed Protein Carbamylation Participates in Asthma. J Biol Chem 291:22118-22135
Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-24
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558
Gu, Xiaodong; Wu, Zhiping; Huang, Ying et al. (2016) A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein. J Biol Chem 291:6386-95
Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2016) Predicting long-term prognosis in stable peripheral artery disease with baseline functional capacity estimated by the Duke Activity Status Index. Am Heart J 184:17-25
Hammadah, Muhammad; Brennan, Marie-Luise; Wu, Yuping et al. (2016) Usefulness of Relative Hypochromia in Risk Stratification for Nonanemic Patients With Chronic Heart Failure. Am J Cardiol 117:1299-304
Senthong, Vichai; Li, Xinmin S; Hudec, Timothy et al. (2016) Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. J Am Coll Cardiol 67:2620-8
Loley, Christina; Alver, Maris; Assimes, Themistocles L et al. (2016) No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis. Sci Rep 6:35278
Paz Y Mar, Hugo L; Hazen, Stanley L; Tracy, Russell P et al. (2016) Effect of Continuous Positive Airway Pressure on Cardiovascular Biomarkers: The Sleep Apnea Stress Randomized Controlled Trial. Chest 150:80-90

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