NITRIC OXIDE/SUPEROXIDE IN LIPID VASCULAR DISEASE

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from Investigator's Abstract): Atherosclerosis is a
leading cause of death in the Western world, and hypercholesterolemia is a
well-known risk factor for its development. Vasomotor abnormalities, in
part due to hypercholesterolemia, are present prior to the onset of overt
atherosclerosis and might play a role in disease progression. The role of
nitric oxide (NO) and superoxide anion in cholesterol-induced vasomotor
dysfunction and atherosclerosis is unclear. NO is generated in the
endothelium by eNOS and can be inactivated with superoxide anions.
Superoxide anions are scavenged by SOD. This project was designed to
determine the role of NO and superoxide in cholesterol-induced vasomotor
dysfunction by overexpressing the genes for eNOS, CuZnSOD and MnSOD in
hypercholesterolemic rabbits. This project is designed to determine the
role of endothelial nitric oxide synthase (eNOS) and superoxide dismutase
(SOD) in cholesterol-induced vasomotor dysfunction by overexpressing the
genes for endothelial eNOS, copper zinc superoxide dismutase (CuZnSOD)and
manganese superoxide dismutase (MnSOD) in the hypercholesterolemic rabbit
carotid artery. The long term goal of this research is to examine the role
of NO and superoxide anion in atherogenesis. eNOS and SOD overexpression
(both isoforms) in the arterial wall of rabbits will be achieved in vivo
using gene transfer with adenoviral vectors. Cholesterol-induced vasomotor
dysfunction will be compared in animals treated with vectors expressing eNOS
and/or SOD and controls. Results from these studies should provide
fundamental information about the roles of NO and superoxide anions in
cholesterol-induced vasomotor dysfunction, and the data might provide useful
information for the development of gene therapy-based strategies for the
treatment of this disorder. The long-term goal of this research is to
examine the role of NO and SOD in atherogenesis. eNOS and SOD
overexpression in arteries will be done in vivo using a gene transfer
technology that employs adenoviral vectors. Cholesterol-induced vasomotor
dysfunction will be compared in animals treated with vectors expressing eNOS
and/or SOD and controls.

Specific Aim 1 is to determine the role of eNOS in cholesterol-induced
vasomotor dysfunction. It is hypothesized that NOS activity and cGMP levels
are reduced in atherosclerotic-induced vasomotor dysfunction and that
restoration of eNOS activity and cGMP levels improves vasomotor responses.

Specific Aim 2 is to determine if SOD is an important regulator of vasomotor
tone. It is hypothesized that adenoviral vectors of SOD attenuate
cholesterol-induced vasomotor dysfunction, and that CuMnSOD is the most
active of the two SOD isoforms.

Specific Aim 3 is to determine the relative roles of eNOS and SOD in
cholesterol-induced vasomotor dysfunction. It is hypothesized that
co-expression of SOD with eNOS will augment vascular relaxation.
StatusFinished
Effective start/end date2/5/981/31/07

Funding

  • National Heart, Lung, and Blood Institute: $100,170.00
  • National Heart, Lung, and Blood Institute: $342,115.00
  • National Heart, Lung, and Blood Institute: $342,560.00
  • National Heart, Lung, and Blood Institute: $343,005.00
  • National Heart, Lung, and Blood Institute: $361,250.00

ASJC

  • Medicine(all)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.