Nitric Oxide-Superoxide in Lipid Induced Vascular Diseas

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Abnormal endothelium dependent
vasorelaxation due to reduced nitric oxide bioavailability in the blood vessel
wall is a key component of vascular disease associated with hyperlipidemia,
hypertension, diabetes mellitus, obesity and atherosclerosis and may be
important in the pathogenesis of atherosclerosis. While there are many
potential causes of decreased NO bioavailability in the blood vessel wall,
decreased NO generation or increased NO degradation via interaction with
superoxide anions may play a pivotal role. Gene therapy approaches to
atherosclerosis may include systemic delivery of genes to the liver to treat
risk factors or local delivery to the vessel wall to enhance NO bioavailability
to augment blood flow, enhance new vessel formation or limit cell proliferation
in the vessel wall. A gene therapy approach utilizing local delivery of NOS
gene to the vessel wall has advantages as nitric oxide has pleiotropic
anti-atherogenic effects in the vasculature. In addition, a better
understanding of the role of superoxide in endothelial dysftinction in various
stages of atherosclerosis may allow the therapeutic effects of superoxide
dismutase overexpression to be explored. In this proposal we will test the
following hypotheses a) individual NOS isoform may have distinct
characteristics for altering vascular reactivity in the normal and diseased
blood vessel wall, b) adeno-associated virus vectors can be used to transfer
the NOS gene to the vascular wall resulting in long term alteration of vascular
reactivity without inflammation and c) long term overexpression of NOS in the
blood vessel wall of the hypercholesterolemic rabbit will improve endothelium
dependent vasorelaxation and delay the progression of atherosclerosis and d)
increased scavenging of superoxide via SOD gene transfer may increase NO
bioavailability and reverse lipid-induced endothelial dysfunction. These
experiments will determine which NOS isoform is best at altering vascular
function, examine the functional effect of prolonged expression of eNOS in the
rabbit carotid artery using AAV vectors, examine the effect of NOS
overexpression on progression of atherosclerosis and elucidate the role of
superoxide in the pathogenesis of endothelial dysfunction in various stages of
StatusNot started


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