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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Fleg, Jerome
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Sithu, Srinivas D; Malovichko, Marina V; Riggs, Krista A et al. (2017) Atherogenesis and metabolic dysregulation in LDL receptor-knockout rats. JCI Insight 2:
Ma, Xiaodong; Conklin, Daniel J; Li, Fenge et al. (2015) The oncogenic microRNA miR-21 promotes regulated necrosis in mice. Nat Commun 6:7151
Zeller, Iris; Srivastava, Sanjay (2014) Macrophage functions in atherosclerosis. Circ Res 115:e83-5
Barski, Oleg A; Xie, Zhengzhi; Baba, Shahid P et al. (2013) Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 33:1162-70
Moreo, Antonella; Ambrosio, Giuseppe; De Chiara, Benedetta et al. (2013) Influence of midwall fibrosis on diastolic dysfunction in non-ischemic cardiomyopathy. Int J Cardiol 163:342-344
Vladykovskaya, Elena; Sithu, Srinivas D; Haberzettl, Petra et al. (2012) Lipid peroxidation product 4-hydroxy-trans-2-nonenal causes endothelial activation by inducing endoplasmic reticulum stress. J Biol Chem 287:11398-409
Vladykovskaya, Elena; Ozhegov, Evgeny; Hoetker, J David et al. (2011) Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids. J Lipid Res 52:2209-25
Ismahil, Mohamed Ameen; Hamid, Tariq; Haberzettl, Petra et al. (2011) Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 301:H2050-60
Srivastava, Sanjay; Sithu, Srinivas D; Vladykovskaya, Elena et al. (2011) Oral exposure to acrolein exacerbates atherosclerosis in apoE-null mice. Atherosclerosis 215:301-8
Amunom, Immaculate; Dieter, Laura J; Tamasi, Viola et al. (2011) Cytochromes P450 catalyze the reduction of ?,?-unsaturated aldehydes. Chem Res Toxicol 24:1223-30

Showing the most recent 10 out of 13 publications