PROJECT SUMMARY/ABSTRACT During abdominal aortic aneurysm (AAA) formation, pathological vascular remodeling is driven by macrophage (Mφs) infiltration, and the mechanisms regulating macrophage-mediated AAA development remain undefined. In the normal aortic wall, a balance exists between matrix metalloproteinases (MMPs), which function to break down the aortic wall, and tissue inhibitors of matrix metalloproteinases (TIMPs), which prevent the actions of MMPs on the aortic wall. However, in a pathologic setting, an imbalance occurs between the MMPs and TIMPs in favor of MMP activity, resulting in AAA development. Although epigenetic mechanisms have been shown to regulate Mφ phenotype in tissues, the regulation of these epigenetic pathways in aortic tissue remains unknown. Our preliminary data identifies that SETDB2, a histone methyltransferase that selectively methylates histone 3 at lysine 9, decreases gene transcription and is increased in murine and human AAA Mφs. Further, we found that JAK1/STAT3 signaling may regulate Setdb2 in aortic Mφs. Considering these findings, we hypothesize that SETDB2 drives AAA formation through a JAK/STAT signaling pathway which shifts Mφs towards a decreased TIMP production, favoring unregulated MMPs and AAA development. This hypothesis will be investigated through the following specific aims: 1) Determine the JAK/STAT/SETDB2-mediated mechanism(s) that regulate Mφ-specific Timp1-3 expression in human and murine AAAs 2) Examine the therapeutic efficacy of Mφ-specific JAK/STAT/SETDB2 inhibition on AAA expansion. In this translational approach, our data will pave the way for the development of promising preventative therapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ inflammation and thereby prevent AAA expansion and rupture.

PROJECT NARRATIVE Abdominal aortic aneurysms (AAAs) are a life-threatening vascular disease responsible for over 15,000 deaths annually that are characterized by immune cells, namely macrophages, that contribute to pathological vascular remodeling. Our preliminary data demonstrate that epigenetic changes in macrophages, driven by JAK/STAT/SETDB2, regulate the activity of metalloproteinases, which function to break down the aortic wall and promote AAA formation. Using both murine models and human specimens, this proposal will seek to understand how these changes develop in aortic tissue and will test new therapies to restore macrophages to homeostasis and prevent AAA expansion.