Grants and Contracts Details
Description
The renin-angiotensin system (RAS) is being increasingly recognized as a direct contributor to the
development of atherosclerosis. I am proposing to test the hypothesis that macrophage specific synthesis of
angiotensin peptides occurs through a renin dependent mechanism under both basal and lipid loaded
conditions and contributes to the development of atherosclerosis. To test this hypothesis, f am proposing the
following specific aims:
Aim 1. Determine the contribution of renin synthesized in macrophages to angiotensin peptide production, and
the contribution of local versus systemic sources to bioactive renin in macrophages. Mouse peritoneal
macrophages (MPMs) from wild type and renin deficient mice will be harvested. Angiotensin peptides in
cultured media will be measured using HPLC prior to quantification by radioimmunoassay. To determine the
contribution of local versus systemic sources to the presence of the renin in these cells, I will use a bone
marrow transfer strategy in which irradiated wild type mice will be repopulated with renin deficient bone
marrow derived cells. The presence of renin in the macrophages of these mice will be compared to mice
repopulated with wild type cells.
Aim 2. Determine whether lipid loading of macrophages alters the contribution of renin to the production of
angiotensin peptides.
The effect of lipid loading on the renin dependence of angiotensin peptide production will be evaluated using
MPMs as described in aim 1. I will determine renin dependency of angiotensin peptide production in MPMs
incubated with AcLDL and an ACA T inhibitor.
Aim 3. Determine the effects of macrophage specific deficiency of renin on the development of atherosclerotic
lesions.
LDL receptor deficient mice will be irradiated and repopulated with bone marrow derived stem cells from either
wild type or renin deficient mice. The effects of deficiency of renin on hypercholesterolemia induced
atherosclerotic lesions will be determined. Atherosclerotic lesions will be quantified and characterized in the
aortic intima and aortic root using the methods that are well established in the Sponsor's laboratory.
Status | Finished |
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Effective start/end date | 7/1/04 → 6/30/06 |
Funding
- American Heart Association Ohio Valley Affiliate: $84,000.00
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