The overall aim of this proposal is to understand the mechanisms by which oxidative stress contributes to ischemic injury in the heart. Our working hypothesis is that reactive oxygen species (ROS) generated during ischemia-reperfusion initiate lipid peroxidation reactions and that unsaturated aldehydes (enals) generated from oxidized lipids trigger and sustain myocardial oxidative stress during ischemia-reperfusion. To asses the contribution of lipid oxidation derived enals we have in the past studied the biochemical pathways of enal metabolism. Our studies show that in the heart enals are metabolized by aldose reductase (AR), aldehyde reductase, and glutathione-S-transferases. Metabolism via AR appears critical because the enzyme is activated during ischemia and inhibition of the enzyme abolishes the cardioprotective effects of ischemic preconditioning. Using AR to interrogate the role of enals in ischemia-reperfusion injury, we now plan to test the hypothesis that accumulation of enals and their protein adducts in the ischemic heart triggers stress responses and cell death. We propose that these responses are mediated in part by endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) and that AR metabolism decreases myocardial injury by diminishing ER stress.
The specific aims of the project are to: (1) delineate the contribution of UPR to enal- induced myocardial injury;(2) elucidate the role of AR in regulating enal-induced ER stress;and (3) to examine the role of AR in preventing ER stress and UPR in hearts subjected to coronary ligation and reperfusion in situ. To accomplish these aims we will examine specific components of the UPR triggered in isolated murine hearts and myocytes, determine how pharmacological inhibition, genetic ablation, or transgenic over expression of AR modify enal-induced UPR. Using a murine model of coronary occlusion, we also plan to study how AR activity and expression levels affect ER stress and UPR during ischemia and reperfusion. We expect that the results obtained from these studies will further our understanding of the nature of ischemic injury and may suggest new ways to prevent tissue injury and dysfunction associated with myocardial infarction.

Public Health Relevance

The aim of this project is to elucidate how ischemia and subsequent reperfusion affects the heart. These studies are of relevance to the understanding of acute myocardial infarction and ischemic heart failure. These diseases are the major cause of death in the U.S. A better understanding of the molecular and cellular mechanisms by which oxidative stress contributes to tissue injury and dysfunction in the ischemic heart may lead to the development of more effective therapeutic interventions to treat heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059378-13
Application #
8085897
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wang, Lan-Hsiang
Project Start
1998-12-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2011
Total Cost
$370,000
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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