Atherosclerosis is the leading cause of death in the USA. As the atherosclerotic deposits grow, they sometimes trigger the formation of clots that block the flow of blood. High level of low-density lipoprotein (LDL) is firmly established as a risk factor for coronary heart disease. Recent studies have indicated that oxidized-LDL (oxi-LDL), probably formed by endothelial cell-mediated lipid peroxidation, is a key component involved in the cellular injury. This modified lipoprotein may directly damage the endothelial cells and results in creased adherence and the migration of monocytes and T-lymphocytes into the subendothelial space. Other studies have shown that Nitric oxide (NO) participates actively in many cellular functions, and the regulation of vasoactivity. It is believed that oxi-LDL interferes with the endothelial production of NO and promotes the formation of atherosclerotic plaques. In this study, we will use the pig aortic endothelial cells to demonstrate that oxi-LDL can alter the production of nitric oxide. The growth inhibitory effect and cytotoxicity of oxi-LDL will also be examined. Next, we will explore the possibility of chemical or physical interventions of these damaging processes initiated by oxi-LDL. A universal adaptive process or stress response that facilitates the cell survival during metabolic trauma can be induced in many living organisms. Previously we had demonstrated that moderate heating of rat heart myocytes reduces cell death in a subsequent oxidative challenge. In this study, similar concept will be applied to trigger the oxidative resistance in the aortic endothelial cells. We will test if heat shock pretreatment of endothelial cells prevents the oxi-LDL effects on their NO production. The endothelial cells will be preconditioned under moderate heating condition (39 degrees C) for 46 days. These heated cells will then be exposed to different concentration of oxi-LDL. The NO release assay and the oxi-LDL cytotoxic effect will be used as criteria for the determination of protection efficiency. The mechanism of this heat-induced protection will be investigated. Increasing evidence has suggested that moderate alcohol consumption reduce the risk of coronary heart disease. The protective mechanism by alcohol remains unclear. It is possible that alcohol induces a similar stress response in the cardiovascular cells that protects them against oxi-LDL toxicity. This possibility will be investigated with chronically conditioned aortic endothelial cells. Information obtained from this study may have its clinical significance in the prevention of atherogenesis.
