Summary assay for small molecule modulators of myocardial damage
Myocardial infarction ("heart attack") is one of the most common causes of morbidity and mortality in the United States and the world1. It is precipitated by acute rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. The sudden cessation of blood flow leads within hours to massive death of heart muscle cells by apoptosis and necrosis1. Prompt myocardial more ..
Depositor Specified Assays
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: 1 R03 DA031671-01
Assay Provider: Richard Kitsis, M.D., Albert Einstein College of Medicine of Yeshiva University
Myocardial infarction ("heart attack") is one of the most common causes of morbidity and mortality in the United States and the world1. It is precipitated by acute rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. The sudden cessation of blood flow leads within hours to massive death of heart muscle cells by apoptosis and necrosis1. Prompt myocardial reperfusion via angioplasty/stenting is currently the optimal treatment, but its effectiveness is limited by a narrow therapeutic time window2,3. Work over the past 25 years in lower organisms and mammals has led to the recognition that a significant portion of cell death - both apoptosis and necrosis - occurs in a deliberate and highly regulated manner4,5. This discovery has prompted re-examination of the possibility that cell death during myocardial infarction can be manipulated. It is hoped that the proposed work will provide the basis for the development of a drug to limit the size of myocardial infarction and/or decrease its speed of progression. it is critical to model both the ischemic and reperfusion phases of myocardial infarction ("ischemia-reperfusion") in a cell-based system. Hydrogen peroxide models the oxidative stress of reperfusion (reperfusion phase), while 2-deoxy-D-glucose, an inhibitor of glycolysis, simulates the metabolic stress of ischemia (ischemic phase). While other death stimuli operate during myocardial infarction in vivo, oxidative stress and the metabolic stress of ischemia would be considered the two most critical of these pathophysiological events in "acute ST-segment elevation myocardial infarction".
1. Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu. Rev. Physiol. 2010;72.
2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13-20.
3. Terkelsen CJ, Christiansen EH, Sorensen JT, Kristensen SD, Lassen JF, Thuesen L, Andersen HR, Vach W, Nielsen TT. Primary PCI as the preferred reperfusion therapy in STEMI: it is a matter of time. Heart. 2009; 95(5):362-369.
4. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205-219.
5. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005;434(7033):652-658.
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.