The atherosclerotic cardiovascular disease is a major cause of mortality such as myocardial infarction. Hypercholesterolemia leads to arterial cholesterol depositions and chronic inflammations. Macrophage/foam cells play a central role in all stage of atherosclerosis because cholesterols are mostly engulfed and further metabolized by macrophages. Macrophage/foam cells also serve as a major source of pro- and anti-inflammatory cytokines that control vascular inflammation response. However, whether hypercholesterolemia causes systemic induction of inflammatory genes are not known. In our transcriptomic profiling of the foam cells isolated from the hypercholesterolemic mice, we identified the members of Guanylate Binding Proteins (GBPs) are significantly elevated. Although it is known GBPs play a role in pathogen-induced inflammation response, no study is reported their role in foam cell biology and atherosclerosis. Our preliminary studies show that GBPs are readily detectable in human and mouse atheroma and blood. In addition, deletions of GBPs reduce inflammatory cytokine secretions and increases a major cholesterol transporter of the foam cells. This suggests that GBPs may be mediators of inflammation and link cholesterol metabolism and inflammation of the foam cells. Thus, using the knock out mice of GBPs deletion, we aim to dissect the molecular mechanism of cholesterol metabolism and inflammation regulated by GBPs and to determine whether deficiency of GBPs are athero-protective or not.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2018 → 06/30/2021|