The overall aim of this grant proposal is to understand the basis of endothelial dysfunction following myocardial ischemia/reperfusion (I/R) injury. We propose that endothelial dysfunction during myocardial I/R injury is caused by over-expression of tumor necrosis factor-alpha (TNF-alpha).
The first aim will casually determine the role of TNF-alpha in endothelial injury following myocardial I/R. We propose that myocardial reperfusion injury to the endothelium will be modest in TNF-alpha knockout (TNF-/-) mice, severe in TNF-alpha over-expression (TNF++/++) mice, and moderate in heterozyqote (TNF-/++, cross of TNF-/- and TNF++/++) mice. We will determine if administration of an antibody to TNF-alpha at the time of reperfusion will prevent endothelial dysfunction as indicated by preservation of endothelial function and maintenance of endothelial barrier function by preventing influx of inflammatory cells. This protocol is designed to mimic a clinically relevant paradigm in which a neutralizing antibody against TNF-alpha could be delivered at the time of a recanalization procedure or restoration of flow following coronary bypass. We will also establish the cell type(s) expressing TNF-alpha during I/R.
The second aim will determine the production and sources of reactive oxygen species (ROS) during basal conditions and during I/R injury.
This aim will establish the link between TNF-alpha and ROS in the induction of endothelial injury following myocardial I/R. We will determine if administration of an antibody to TNF-alpha at the time of reperfusion will prevent ROS generation. We will establish if the production of ROS is elevated in TNF++/++ mice, or is reduced in TNF mice. We further propose that TNF-alpha will stimulate production of these chemical species by activation of xanthine oxidase and NADPH oxidase. We will also establish the link between TNF-alpha and the activation of superoxide generating enzymes using electron paramagnetic resonance spectroscopy to quantitatively measure O2. production from coronary arterioles during exposure to varying doses of TNF-alpha.
The third aim will determine if TNF-alpha expression affects the expression of arginase in endothelial cells.
This aim will focus on the proposition that TNF++/++ mice will show elevated arginase expression;whereas, TNF-/- mice will demonstrate reduced levels of arginase expression compared to WT control animals. We utilize a combination of approaches involving in vitro microscopy, fluorescence and EPR analysis of O2. production, electrochemical detection of authentic NO, real time PCR of RNA transcripts, and Western Blotting to evaluate expression of key proteins in the models. We believe that this study will provide a new approach for the treatment of I/R injury and related disorders (post-bypass complications). It is our goal that these studies will provide a clear understanding of the basis for endothelial dysfunction following I/R injury and we hope that this better understanding will facilitate new avenues of therapy to combat this complication.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077566-05
Application #
7796786
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2006-06-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$357,347
Indirect Cost
Name
University of Missouri-Columbia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Chen, Xiuping; Zhang, Hanrui; Hill, Michael A et al. (2015) Regulation of Coronary Endothelial Function by Interactions between TNF-?, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice. J Vasc Res 52:372-82
Li, Jun; Zhang, Hanrui; Zhang, Cuihua (2012) Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications. J Mol Cell Cardiol 52:865-72
Zhang, Hanrui; Dellsperger, Kevin C; Zhang, Cuihua (2012) The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol 107:237
Lee, Sewon; Zhang, Hanrui; Chen, Jianping et al. (2012) Adiponectin abates diabetes-induced endothelial dysfunction by suppressing oxidative stress, adhesion molecules, and inflammation in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 303:H106-15
Park, Yoonjung; Booth, Frank W; Lee, Sewon et al. (2012) Physical activity opposes coronary vascular dysfunction induced during high fat feeding in mice. J Physiol 590:4255-68
Zhang, Hanrui; Zhang, Cuihua (2012) Vasoprotection by dietary supplements and exercise: role of TNF? signaling. Exp Diabetes Res 2012:972679
Zuidema, Mozow Y; Dellsperger, Kevin C (2012) Myocardial Stunning with Hemodialysis: Clinical Challenges of the Cardiorenal Patient. Cardiorenal Med 2:125-133
Lee, Sewon; Park, Yoonjung; Zhang, Cuihua (2011) Exercise Training Prevents Coronary Endothelial Dysfunction in Type 2 Diabetic Mice. Am J Biomed Sci 3:241-252
Zhang, Cuihua (2011) Cardiovascular physiology at the bench for application in the clinic. World J Cardiol 3:59-64
Zhang, Hanrui; Potter, Barry J; Cao, Ji-Min et al. (2011) Interferon-gamma induced adipose tissue inflammation is linked to endothelial dysfunction in type 2 diabetic mice. Basic Res Cardiol 106:1135-45

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