The long-term goal of this project is to assess the contribution of lipid peroxidation to atherogenesis and to understand the mechanisms by which the products of lipid peroxidation contribute to the formation of atherosclerotic lesions. Previous studies have shown that the oxidation of low-density lipoprotein (LDL) generates toxic aldehydes, which could trigger and sustain the formation of atherosclerotic lesions. However, the contribution of these aldehydes to atherogenesis is unclear, and the mechanism by which they are metabolized and detoxified in the endothelium have not been examined. The intent of this project is to examine the endothelial metabolism of the LDL-derived aldehydes and to delineate their contribution to the initiation and the development of atherosclerotic lesions. To examine the biochemical processes that metabolize these aldehydes we will use 1-palmitoyl-2-(-5-oxovaleryl)-3-glycero phosphocholine (POVPC) and 4-hydroxy-trans-2-nonenal (HNE) as model aldehydes. These aldehydes respresent the most abundant esterified and non-esterified aldehydes generated during the oxidation of LDL. Our central hypothesis is that the polyol pathway enzyme aldose reductase (AR) catalyzes the major reductive pathway, common to the detoxification of both the esterified and non-esterifled aldehydes, and the AR-catalyzed pathway protects against the atherogenic effects of oxidized LDL. To test this hypothesis, in Aim 1, we will identify, quantify, and characterize the major products of POVPC and HNE in human endothelial cells in culture. To delineate the contribution of AR, in Aim 2, we will examine changes in the rate and extent of formaiton of the major metabolites in the presence of aldose reductase inhibitors and investigate the relationship between aldose reductase and other pathways of aldehyde metabolism due to phospholipases, platelet activating factor-acetylhydrolase and aldehyde dehydrogenase. To assess the toxicological significance of the aldose reductase-catalyzed pathway, we will examine whether inhibition of this enzyme enhances the extent of induction of the adhesion molecules ICAM-1 and VCAM in endothelial cells and increases the adhesion of monocytes to endothelial cells in culture.
In Aim 3, we will examine the development of atherosclerotic lesions in apoE and LDL-receptor null mice and determine whether inhibition of aldose reductase exacerbates pre-atherosclerotic changes and increases the arterial abunbance of ICAM-1 and VCAM and whether this accelerates the formation of atherosclerotic lesions. The results of these studies will provide a better understanding of the mechanisms by which phospholipid oxidation promotes atherosclerosis, amd may lead to the identification of a novel pathway regulating the extent and the severity of arterial lesions. These studies could also form the basis of future assessments of individual risk for atherosclerosis due to differences in the vascular metabolism of aldehydes.
| States, J Christopher; Srivastava, Sanjay; Chen, Yu et al. (2009) Arsenic and cardiovascular disease. Toxicol Sci 107:312-23 |
| Haberzettl, Petra; Vladykovskaya, Elena; Srivastava, Sanjay et al. (2009) Role of endoplasmic reticulum stress in acrolein-induced endothelial activation. Toxicol Appl Pharmacol 234:14-24 |
| Spite, M; Summers, L; Porter, T F et al. (2009) Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress. Br J Pharmacol 158:1062-73 |
| Keith, Rachel J; Haberzettl, Petra; Vladykovskaya, Elena et al. (2009) Aldose reductase decreases endoplasmic reticulum stress in ischemic hearts. Chem Biol Interact 178:242-9 |
| Srivastava, Sanjay; Vladykovskaya, Elena N; Haberzettl, Petra et al. (2009) Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE-/- mice. Toxicol Appl Pharmacol 241:90-100 |
| Hill, Bradford G; Awe, Sunday O; Vladykovskaya, Elena et al. (2009) Myocardial ischaemia inhibits mitochondrial metabolism of 4-hydroxy-trans-2-nonenal. Biochem J 417:513-24 |
| Hill, Bradford G; Haberzettl, Petra; Ahmed, Yonis et al. (2008) Unsaturated lipid peroxidation-derived aldehydes activate autophagy in vascular smooth-muscle cells. Biochem J 410:525-34 |
| Kaiserova, Karin; Tang, Xian-Liang; Srivastava, Sanjay et al. (2008) Role of nitric oxide in regulating aldose reductase activation in the ischemic heart. J Biol Chem 283:9101-12 |
| Srivastava, Sanjay; Chandrasekar, Bysani; Gu, Yan et al. (2007) Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res 74:445-55 |
| Srivastava, Sanjay; D'Souza, Stanley E; Sen, Utpal et al. (2007) In utero arsenic exposure induces early onset of atherosclerosis in ApoE-/- mice. Reprod Toxicol 23:449-56 |
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