Alex Sevanian, Ph.D.

Molecular Pharmacology and Toxicology

Redox events in cell signaling and atherosclerosis

Oxidative events are recognized as important mediators of cell function where the redox status of enzymes, receptor proteins or even coupled metabolic processes governs their activities. Cell signaling events are not only controlled through expression of proteins and other molecules, or by the post-transcriptional state of proteins, but by their redox status. This appears to involve catalytic oxidation and reduction of the molecules, and in certain proteins, signal transduction can be modulated by the oxidation status of specific amino acids. This modulation is governed by the activity of oxido-reductase enzymes. This redox control is also affected by antioxidants, or more precisely, by the relative activities of antioxidants vs pro-oxidant reactions in cells. An imbalance in pro- vs anti-oxidant activity is now regarded as the basis for oxidant-mediated injury and for pathological states arising from oxidative stress.

Our laboratory investigates the effects of redox status on cell signaling events that are linked to the metabolism of lipids and lipoproteins. Principal among these is the protein kinase-mediated activation of lipolytic enzymes that regulate the turnover and interconversions of phospholipids and cholesterol. The effects of oxidants on kinase-mediated activation of enzymes such as phospholipase A2 and acylCoA-cholesteryl acyltransferase are being studied since these enzymes are highly responsive to membrane phospholipid and cholesterol oxidation. The activities of these and related enzymes are enhanced under pro-oxidant conditions, reduced by antioxidants, and modulated by a host of oxido-reductase enzyme activities. The biomedical relevance of this work is directed to the area of atherosclerosis research since there is mounting evidence that lipoprotein oxidation and oxidative stress to vascular cells facilitate early vascular lesion formation which develop into atherosclerotic plaques. Basic and clinical studies are underway to evaluate how lipoprotein oxidation and specific oxidized lipids evoke atherogenic responses in vascular cells through signaling processes noted above.

Selected Publications

1. Sevanian A, Hodis HN, Hwang J, McLeod, LL and Peterson H: Characterization of endothelial cell injury by cholesterol oxidation products found in oxidized LDL. J. Lipid Res. 36:1971-1986, 1995.
2. Sweetman LL, Zhang N, Peterson H, McLeod LL and Sevanian A: Effect of linoleic acid hydroperoxide on endothelial cell calcium homeostasis and arachidonic acid release. Arch Biochem Biophys. 323:97-107, 1995.
3. Sevanian A, Hwang J, Hodis HN, Cazzolato G, Avogaro P and Bittolo-Bon G: Association of an in vivo circulating oxidized low density lipoprotein (LDL-) with dense LDL subpopulations and its contribution to LDL oxidation. Arterioscleros Thrombos 16:784-793, 1996.