Grants and Contracts Details
Description
Mice deficient in scavenger receptor class BI (SR-BI) or endothelial nitric oxide synthase (eNOS) develop
atherosclerosis, however mice over expressing SR-BI or eNOS also develop atherosclerosis, indicating that
balanced expression of SR-BI or eNOS is essential for preventing atherosclerosis. We recently identify a novel
apoptotic pathway in endothelial cells that is induced by SR-BI and specifically suppressed by eNOS. We also
show that SR-BI stimulates eNOS to produce 5 folds more nitric oxide. The dramatic increase in nitric oxide
level, especially in caveolae, can be a problem because nitric oxide can cause cell damage at high levels.
Interestingly, our preliminary data show that SR-BI efficiently prevents nitric oxide-induced cell death. These
data indicate that SR-BI and eNOS work together in a co-regulatory manner. The goal of this proposal is to
elucidate how SR-BI and eNOS regulate each other, and their respective contribution in preventing endothelial
cell dysfunction. Our hypothesis is:
SR-BI and eNOS work cooperatively through a novel SR-BlleNOS apoptotic pathway and a SR-Bl/nitric oxide
scavenger pathway to prevent vascular endothelial cell dysfunction.
We will perform binding assays and apoptotic assays using in vitro cell lines expressing mutant SR-BI and
primary endothelial cells from genetically manipulated mice. We will also perform in situ assays using aorta
from genetically manipulated mice to test the following specific aims:
Aim 1) To elucidate the mechanism of how eNOS turns off SR-BI-induced apoptosis in healthy cells;
Aim 2) To elucidate the mechanism of how eNOS turns on SR-BI-induced apoptosis in damaged cells;
Aim 3) To elucidate the mechanism of how SR-BI prevents nitric oxide-induced cell damage.
Atherosclerosis is a multi-genes-controlled complex disease and vascular endothelial cell dysfunction is the
earliest signs of developing atherosclerosis. The unique part of this proposal is that we provide evidence to
show that two caveolae proteins, SR-BI and eNOS, are linked by two different pathways. Understanding the
novel SR-BlleNOS apoptotic pathway and SR-Bllnitric oxide scavenger pathway will provide insight into the
mechanisms of atherosclerosis and reveal novel targets for disease intervention.
Status | Finished |
---|---|
Effective start/end date | 1/1/05 → 12/31/07 |
Funding
- American Heart Association: $66,013.00
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