دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.
المؤلفون: Davis FM; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Melvin WJ; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Mangum K; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Tsoi LC; Department of Dermatology, University of Michigan, Ann Arbor, MI.; Department of Computation Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.; Department of Biostatistics, University of Michigan, Ann Arbor, MI., Joshi AD; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Cai Q; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Henke PK; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI., Gudjonsson JE; Department of Dermatology, University of Michigan, Ann Arbor, MI., Gallagher KA; Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI.; Department of Pathology, University of Michigan, Ann Arbor, MI.; Department Microbiology and Immunology, University of Michigan, Ann Arbor, MI.
المصدر: Annals of surgery [Ann Surg] 2023 Sep 01; Vol. 278 (3), pp. 426-440. Date of Electronic Publication: 2023 Jun 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0372354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-1140 (Electronic) Linking ISSN: 00034932 NLM ISO Abbreviation: Ann Surg Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : Lippincott Williams & Wilkins
مواضيع طبية MeSH: Aortic Aneurysm, Abdominal*/genetics , Aortic Aneurysm, Abdominal*/pathology , Histones*/adverse effects , Histones*/metabolism , Tissue Inhibitor of Metalloproteinase-3*/genetics, Animals ; Humans ; Mice ; Angiotensin II/adverse effects ; Angiotensin II/metabolism ; Aorta, Abdominal/pathology ; Disease Models, Animal ; Histone Methyltransferases/metabolism ; Janus Kinases/adverse effects ; Janus Kinases/metabolism ; Lysine/adverse effects ; Lysine/metabolism ; Matrix Metalloproteinases/adverse effects ; Matrix Metalloproteinases/metabolism ; Mice, Inbred C57BL ; Mice, Knockout
مستخلص: 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.
Competing Interests: The authors report no conflicts of interest.
(Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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معلومات مُعتمدة: R01 DK131782 United States DK NIDDK NIH HHS; P30 AR075043 United States AR NIAMS NIH HHS; R01 HL156274 United States HL NHLBI NIH HHS; R35 HL167143 United States HL NHLBI NIH HHS; F32 DK117545 United States DK NIDDK NIH HHS; R01 AR069071 United States AR NIAMS NIH HHS
المشرفين على المادة: 11128-99-7 (Angiotensin II)
EC 2.1.1.- (Histone Methyltransferases)
0 (Histones)
EC 2.7.10.2 (Janus Kinases)
K3Z4F929H6 (Lysine)
EC 3.4.24.- (Matrix Metalloproteinases)
0 (Timp1 protein, mouse)
0 (Timp2 protein, mouse)
0 (Tissue Inhibitor of Metalloproteinase-3)
EC 2.1.1.43 (Setdb2 protein, mouse)
تواريخ الأحداث: Date Created: 20230616 Date Completed: 20230811 Latest Revision: 20240430
رمز التحديث: 20240430
مُعرف محوري في PubMed: PMC10526639
DOI: 10.1097/SLA.0000000000005963
PMID: 37325923
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-1140
DOI:10.1097/SLA.0000000000005963