Cholesterol-dependent Gene Regulation of Vascular Function

Grant Winners

Deans

Abstract

Coronary heart disease is the leading cause of morbidity and mortality worldwide. It has been unequivocally shown that lowering of blood cholesterol levels reduces cardiovascular events and the development of atherosclerosis. In addition of the pathogenic role of blood cholesterol, the endogenous production of cholesterol by vascular cells impacts vascular health. Inhibition of the cholesterol synthetic pathway in vascular cells facilitates the production of vascular-protective substances, while inhibiting the production of substances with vascular-deleterious actions. Conversely, activation of the cholesterol synthetic pathway leads to severe vascular dysfunction. The interactions between changes in cholesterol synthesis in vascular cells and vascular function are poorly understood.

The objective of this application is to determine in vascular endothelial and smooth muscle cells which of the genes that code for vascular protective and vascular deleterious substances are sensitive to modulation by changes in cholesterol synthesis. Our central hypothesis is that in addition to high blood cholesterol, a high rate of cholesterol synthesis in vascular cells affects vascular function. We propose that this is achieved through the activation of genes coding for substances with vascular constrictive, growth-promoting and pro-inflammatory activities. Microarrays will be employed to detect up-regulation and/or down-regulation of gene expression induced by treatments that inhibit or stimulate the cholesterol synthetic pathway.

Completion of this proposal will help in determining which genes participate in inducing vascular dysfunction when the cholesterol synthetic pathway is activated. Identifying these genes is fundamental to design new therapeutic interventions, and to better comprehend the regulation of vascular function.