Cardiovascular disease is the major cause of death in the United States with most of the morbidity and mortality resulting from plaque rupture. Strokes account for approximately 157,000 of those deaths each year. As the majority of strokes result from plaque rupture, elucidating the differences between vulnerable and stable plaques will aid in the design of therapies to stabilize vulnerable plaques. To this end, we have compared the expression of 21 genes in stable (femoral) and unstable (carotid) plaques obtained from endarterectomy. Not surprisingly, genes involved in the breakdown of the extracellular matrix were elevated in the unstable plaques. Interestingly, components of the Fc? receptor signaling pathway, including Fc?RI, Fc?Rlla, and Fc?RIII are dramatically higher in unstable compared to stable plaques. In vitro studies using human macrophages incubated with immune complexes or C reactive protein (to ligate Fc?R receptors) recapitulated the expression profile of the unstable plaque tissue. These data suggest that the Fc?R- mediated signaling network is upregulated in unstable plaques and may contribute to plaque progression and/or instability. If true, treatments to decrease Fc?R signaling may provide a novel approach for stabilizing vulnerable plaques. However, the role of Fc?R in plaque progression and vulnerability has yet to be determined. That is the subject of this application.
Three specific aims will test the hypothesis that Fc?R contribute to the vulnerability and/or development of carotid plaques.
Aim I) Plaque stability in Apo E -/- mice expressing none or all of the activating Fc?R will be quantified using 6 standard measures of plaque vulnerability, including lipid accumulation, intraplaque hemorrhage, plaque rupture, and thin cap fibroatheroma, Aim II) the effect of Fc?R expression on gene expression profiles will be determined and compared to those of stable and unstable human plaques, and Aim III) the effect of Fc?R expression on plaque development will be followed longitudinally using non-invasive, small animal ultrasound biomicroscopy. Completion of these studies will resolve the question of the involvement of Fc?R in plaque progression and/or vulnerability and establish the validity of the model as representative of human carotid plaque pathology. The results will provide the rationale for subsequent studies identifying Fc?R induced plaque instability genes and assessing the effects of downregulating such genes on carotid plaque progression and vulnerability. Project Narrative: In the United State, 3 people die from heart disease every minute with plaque rupture contributing to the majority of those deaths. Our data suggest that FcR signaling in involved in the development of unstable plaques. This research will determine the role of Fc?R in plaque progression and rupture and provide novel targets for reducing heart attack and stroke. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL089730-01A2
Application #
7532640
Study Section
Special Emphasis Panel (ZRG1-CVS-Q (90))
Program Officer
Srinivas, Pothur R
Project Start
2008-08-15
Project End
2010-05-31
Budget Start
2008-08-15
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$233,301
Indirect Cost
Name
Albany Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Ng, Hang Pong; Zhu, Xinmei; Harmon, Erin Y et al. (2015) Reduced Atherosclerosis in apoE-inhibitory Fc?RIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages. Arterioscler Thromb Vasc Biol 35:1101-12
Harmon, Erin Y; Fronhofer 3rd, Van; Keller, Rebecca S et al. (2014) Anti-inflammatory immune skewing is atheroprotective: Apoe?/?Fc?RIIb?/? mice develop fibrous carotid plaques. J Am Heart Assoc 3:e001232
Harmon, Erin Y; Fronhofer, Van; Keller, Rebecca S et al. (2012) Ultrasound biomicroscopy for longitudinal studies of carotid plaque development in mice: validation with histological endpoints. PLoS One 7:e29944
Loegering, Daniel J; Lennartz, Michelle R (2011) Protein kinase C and toll-like receptor signaling. Enzyme Res 2011:537821
Lennartz, Michelle R; Aggarwal, Ankur; Michaud, Tanya M et al. (2011) Ligation of macrophage Fc? receptors recapitulates the gene expression pattern of vulnerable human carotid plaques. PLoS One 6:e21803