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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Hasan, Ahmed AK
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361
Arif, Abul; Jia, Jie; Halawani, Dalia et al. (2017) Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation. Methods 113:72-82
Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2017) 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
Hirbawi, Jamila; Bialkowska, Katarzyna; Bledzka, Kamila M et al. (2017) The extreme C-terminal region of kindlin-2 is critical to its regulation of integrin activation. J Biol Chem 292:14258-14269
Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius et al. (2017) Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol 5:534-543
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2017) The GAIT translational control system. Wiley Interdiscip Rev RNA :
Brown, J Mark; Hazen, Stanley L (2017) Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery. J Biol Chem 292:8560-8568
Pamir, Nathalie; Hutchins, Patrick M; Ronsein, Graziella E et al. (2017) Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI Insight 2:
Mollenhauer, Martin; Friedrichs, Kai; Lange, Max et al. (2017) Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling. Circ Res 121:56-70
Tang, W H Wilson; Wang, Zeneng; Li, Xinmin S et al. (2017) Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem 63:297-306

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