The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase–Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development

Objective: To determine macrophage-specific alterations in epigenetic enzyme function contributing to development of abdominal aortic aneurysms (AAAs). Summary Background Data: AAA are a life-threatening disease, characterized by pathological vascular remodeling driven by an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. Methods: The role of SETDB2 in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. Results: Single-cell RNA sequencing of human AAA tissues, identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared to controls. Mechanistically, interferon-β regulates Setdb2 expression via JAK/STAT signaling which trimethylates histone 3 lysine 9 (H3K9) on the TIMP1-3 gene promoters thereby suppressing Timp1-3 transcription and leading to unregulated MMP activity. Macrophage-specific knockout of SETDB2 ( Setdb2 f/f Lyz2 Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to removal of the repressive H3K9-trimethylation mark on the Timp1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the JAK/STAT pathway with an FDA approved inhibitor, Tofacitinib, limited Setdb2 expression in aortic macrophages. Conclusions: These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.