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

Abstract

OBJECTIVE:

To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs).

BACKGROUND:

AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases 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 SET Domain Bifurcated Histone Lysine Methyltransferase 2 (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 with controls. Mechanistically, interferon-β regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription 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.

• Authors: Frank M Davis, William J Melvin, Kevin Mangum, Lam C Tsoi, Amrita D Joshi, Qing Cai, Peter K Henke, Johann E Gudjonsson, Katherine A Gallagher
• Journal: Annals of surgery (Ann Surg) Vol. 278 Issue 3 Pg. 426-440 (09 01 2023) ISSN: 1528-1140 [Electronic] United States
• PMID: 37325923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Angiotensin II
• Histone Methyltransferases
• Histones
• Janus Kinases
• Lysine
• Matrix Metalloproteinases
• Timp1 protein, mouse
• Timp2 protein, mouse
• Tissue Inhibitor of Metalloproteinase-3
• Setdb2 protein, mouse

Topics

• Animals
• Humans
• Mice
• Angiotensin II (adverse effects, metabolism)
• Aorta, Abdominal (pathology)
• Aortic Aneurysm, Abdominal (genetics, pathology)
• Disease Models, Animal
• Histone Methyltransferases (metabolism)
• Histones (adverse effects, metabolism)
• Janus Kinases (adverse effects, metabolism)
• Lysine (adverse effects, metabolism)
• Matrix Metalloproteinases (adverse effects, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Tissue Inhibitor of Metalloproteinase-3 (genetics)