The overall goal of this project is to understand the role of lipid peroxidation-derived aldehydes in atherosclerosis. Aldehydes such as 4-hydroxynonenal (HNE) and 1-palmitoyl-2-(5-oxovaleroyl)-3- glycero- phosphatidyl choline (POVPC) are the major bioactive products generated from the oxidation of LDL. Based on supportive preliminary studies, we propose to test hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR), leading to cytokine production and foam cell formation.
The specific aims of this project are to: (1) delineate the contribution of ER stress and UPR to aldehyde-mediated macrophage activation;(2) elucidate the role of UPR in regulating atherogenesis;and (3) examine the role of aldehyde metabolism in preventing ER stress and UPR in atherosclerotic lesions. To accomplish these aims, we will examine whether exposure of murine bone marrow derived macrophages to model lipid-derived aldehydes - HNE or POVPC induces ER stress and UPR. We will determine the extent and the nature of this response and identify which specific UPR-dependent signaling pathways are activated by aldehydes and how they contribute to macrophage activation, foam cell formation, and apoptosis. To examine the role of ER-stress and UPR during atherosclerotic lesion formation, we will determine stage-specific changes in ER stress and UPR in the arterial lesions of apoE-null mice. To probe causality, we will examine whether treatment with chemical chaperones, which assist protein folding, would decrease lesion formation and improve plaque stability. In addition, we will test whether genetic ablation of activating factor 3 (ATF3), a UPR-responsive gene, which is dramatically induced by lipid aldehydes, increases lesion progression and inflammation. To elucidate the role of aldehydes in inducing ER stress in atherosclerotic lesions, we will examine how genetic deletion or overexpression of aldose reductase, an enzyme which detoxifies both HNE and POVPC, affects aldehyde-induced macrophage activation and foam cell formation in culture and ER stress, UPR induction in the arterial lesions of apoE-null mice. Successful completion of this project may lead to a better understanding of the mechanisms by which lipid-derived aldehydes affect atherogenesis and how the effects of these aldehydes could be prevented or therapeutically minimized to decrease atherosclerosis.

Public Health Relevance

Oxidized lipids have been suggested to play a pivotal role in the formation of atherosclerotic lesions, nevertheless, the mechanisms by which these lipids or their products induce vascular injury, and promote plaque formation or rupture are unknown. Our studies are designed to test the hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticular (ER) stress and triggers unfolded protein response (UPR). We propose that lipid-derived aldehydes induce the transcription factor 3 (ATF3), which is associated with the alarm phase of UPR and genetic ablation of ATF3 exacerbates and pharmacological inhibition of ER-stress decreases atherogenesis. To examine that aldehydes are indeed causally involved in ER-stress and atherogenesis, we will examine whether macrophage specific overexpression or deletion of aldose reductase, which converts toxic aldehydes to innocuous alcohols, affects their atherogenic effects. Results obtained from this project will help in developing a better understanding, and potentially, novel therapeutic strategies for decreasing or managing atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL095593-01A1
Application #
7791087
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Domanski, Michael
Project Start
2010-03-15
Project End
2014-02-28
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$372,500
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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