The objective of this Program Project is to define the mechanisms of inflammation and repair in the heart after ischemia and reperfusion. The Projects focus on transcription factors and radical messenger molecules that mediate the response to ischemia and reperfusion in vascular endothelial cells and cardiomyoctes. The specific objectives are to determine the following: (1) the molecular mechanisms that activate production of superoxide and nitric oxide in the heart following ischemia, (2) the role of the adaptor protein p66shc in mediating post-ischemic oxidant generation and myocardial injury, (3) the role of the transcription factor Stat3 in mediating the inflammatory response to myocardial ischemia-reperfusion injury, (4) the role of endothelial cell exocytosis in mediating inflammation after ischemia-reperfusion, and (5) the role of the transcription factor HIF-1 and its target gene products in protecting and repairing the heart after ischemia. The Program Project has 5 Projects and 3 Cores (Pathology, Animal, and Administrative/Statistical). The Projects will perform studies with purified proteins, cultured cells, isolated perfused hearts, and in-vivo murine animal models. The techniques will include molecular biology, gene expression profiling with cDNA arrays, gene transfer by recombinant adenoviral vectors, transfection of decoy oligonucleotides or interfering RNAs, use of bone marrow derived stromal cells, and use of mice with targeted genetic mutations. The Cores will provide histology, immunohistology, fluorescent confocal microscopy, and murine models of (1) myocardial ischemia-reperfusion with measurement of infarct size and assessment of left ventricular function by echocardiography and pressure-volume loops and (2) post-ischemic inflammation of the cremaster muscle with assessment of leukocyte trafficking by computer-assisted videomicroscopy. We anticipate that this Program Project will yield fundamental information about the cellular mechanisms of post-ischemic inflammation and cardiac repair, and will provide novel therapeutic approaches to reducing post-ischemic myocardial injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL065608-10
Application #
7797986
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liang, Isabella Y
Project Start
2000-09-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
10
Fiscal Year
2010
Total Cost
$2,570,374
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Velayutham, Murugesan; Hemann, Craig F; Cardounel, Arturo J et al. (2016) Sulfite Oxidase Activity of Cytochrome c: Role of Hydrogen Peroxide. Biochem Biophys Rep 5:96-104
Long 3rd, Victor P; Bonilla, Ingrid M; Vargas-Pinto, Pedro et al. (2015) Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci 123:61-71
Xie, Lin; Talukder, M A Hassan; Sun, Jian et al. (2015) Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J Mol Cell Cardiol 86:14-22
Reyes, Levy A; Boslett, James; Varadharaj, Saradhadevi et al. (2015) Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart. Proc Natl Acad Sci U S A 112:11648-53
Joddar, Binata; Firstenberg, Michael S; Reen, Rashmeet K et al. (2015) Arterial levels of oxygen stimulate intimal hyperplasia in human saphenous veins via a ROS-dependent mechanism. PLoS One 10:e0120301
Moldovan, Nicanor I; Anghelina, Mirela; Varadharaj, Saradhadevi et al. (2014) Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction. J Am Heart Assoc 3:e000471
Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101
Chen, Yeong-Renn; Zweier, Jay L (2014) Cardiac mitochondria and reactive oxygen species generation. Circ Res 114:524-37
Tong, Jianjing; Zweier, Joseph R; Huskey, Rachael L et al. (2014) Effect of temperature, pH and heme ligands on the reduction of Cygb(Fe(3+)) by ascorbate. Arch Biochem Biophys 554:1-5
Lee, Masaichi-Chang-Il; Velayutham, Murugesan; Komatsu, Tomoko et al. (2014) Measurement and characterization of superoxide generation from xanthine dehydrogenase: a redox-regulated pathway of radical generation in ischemic tissues. Biochemistry 53:6615-23

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