It is now well recognized that the clinical manifestations of coronary artery disease are due to a fundamental lapse in vascular homeostasis. This process begins with the rupture of an atherosclerotic plaque. Following this event, there is a cascade of events characterized by local platelet adhesion, platelet activation, thrombosis, and associated vasospasm. The precise molecular events that render an atherosclerotic plaque vulnerable to rupture are at present unknown. The purpose of this collaborative proposal is to help shed light on the molecular and physical mechanisms of plaque rupture. Convincing data demonstrate that plaque rupture is associated with vascular inflammation. Principal mediators of vascular inflammation are cell adhesion molecules and reactive oxygen species. Project 1 of this proposal will examine the relationship between cellular antioxidant status and the adhesiveness of inflammatory cells and platelets. This link between reactive oxygen species and the vulnerable plaque will be further extended to the process of thrombosis in Project 2 of this collaborative proposal. Because it is known that vulnerable plaques also possess specific physical characteristics, in Project 3 we will use an animal model of plaque rupture and atherosclerosis to correlate physical characteristics of vulnerable plaques, as defined by NMR spectroscopy and MRI, to their propensity for rupture. Finally, we will use the well characterized Framingham Heart Study population to examine the relationship between inflammatory markers of vascular disease and a well recognized surrogate marker of vascular disease, namely endothelial function. Using this multidisciplinary approach, we anticipate developing important new information to help shed light on the molecular mechanisms of plaque rupture, the associated physical characteristics of the vulnerable plaque, and the thrombotic and inflammatory responses to plaque rupture.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061795-02
Application #
6078048
Study Section
Special Emphasis Panel (ZHL1-CSR-B (S1))
Project Start
1998-09-30
Project End
2002-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Libby, Peter; Loscalzo, Joseph; Ridker, Paul M et al. (2018) Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol 72:2071-2081
Yang, Jia-Shu; Hsu, Jia-Wei; Park, Seung-Yeol et al. (2018) GAPDH inhibits intracellular pathways during starvation for cellular energy homeostasis. Nature 561:263-267
Schlotter, Florian; Halu, Arda; Goto, Shinji et al. (2018) Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease. Circulation 138:377-393
Cranford, Jonathan P; O'Hara, Thomas J; Villongco, Christopher T et al. (2018) Efficient Computational Modeling of Human Ventricular Activation and Its Electrocardiographic Representation: A Sensitivity Study. Cardiovasc Eng Technol 9:447-467
Musri, Melina M; Coll-Bonfill, NĂºria; Maron, Bradley A et al. (2018) MicroRNA Dysregulation in Pulmonary Arteries from Chronic Obstructive Pulmonary Disease. Relationships with Vascular Remodeling. Am J Respir Cell Mol Biol 59:490-499
Wang, Rui-Sheng; Loscalzo, Joseph (2018) Network-Based Disease Module Discovery by a Novel Seed Connector Algorithm with Pathobiological Implications. J Mol Biol 430:2939-2950
Leopold, Jane A; Loscalzo, Joseph (2018) Emerging Role of Precision Medicine in Cardiovascular Disease. Circ Res 122:1302-1315
Oldham, William M; Oliveira, Rudolf K F; Wang, Rui-Sheng et al. (2018) Network Analysis to Risk Stratify Patients With Exercise Intolerance. Circ Res 122:864-876
Divakaran, Sanjay; Loscalzo, Joseph (2017) The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics. J Am Coll Cardiol 70:2393-2410
Flier, Jeffrey S; Loscalzo, Joseph (2017) Categorizing biomedical research: the basics of translation. FASEB J 31:3210-3215

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