Annual Grant Winners 2004-2005
Luigi Cubeddu, Ph.D., HPD – College
Grady Campbell, Ph.D., HPD – College
of Medical Sciences
Dean William Hardigan, HPD – College of Pharmacy
Dean Harold Laubach, HPD – College
of Medical Sciences
Gene Regulation of Vascular Function
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
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.