Fellowship Hong Lu: Renin-Dependent Angiotensin Peptide Generation in Macrophages and its Contribution to Hypercholesterolemia Induced Atherosclerosis

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.
StatusFinished
Effective start/end date7/1/046/30/06

Funding

  • American Heart Association Ohio Valley Affiliate: $84,000.00

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.