Cardiovascular disease is the major cause of death in the United States with much 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, FcgRlla, 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? 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. We can induce stable and unstable carotid plaques in atherosclerosis-prone Apo E-/- mice by implanting constrictive cuffs or casts with different geometries. Cast and cuffs will be implanted in Apo E-/- mice expressing activating or inhibitory Fc?R. Using these two models on mice expressing different types of Fc? R , we will test the hypothesis that activating Fc?R are involved in the formation and/or stability of carotid atherosclerotic plaques. I) The effect of Fc?R expression on stable and unstable plaque development will be determined using ultrasound biomicroscopy. II) Histology will be used to determine the effect of Fc? R expression on plaque stability. III) Quantitivative RT-PCR will be used to determine the expression of plaque instability genes in mice expressing different complements of Fc?R. This application details a comprehensive and novel approach to the study of stroke. Successful completion will identify genes that are differentially expressed in stable vs unstable plaques and the role of the activating and inhibitory Fc?R on that expression. The results will provide sufficient preliminary data for an R01 aimed at using viral transduction to selectively modify """"""""plaque instability genes"""""""" in an effort to stabilize vulnerable plaques.
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 FcgR in plaque progression and rupture and provide novel targets for reducing heart attack and stroke.
|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|