دورية أكاديمية
The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.
العنوان: | The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development. |
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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 |
تدمد: | 1528-1140 |
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DOI: | 10.1097/SLA.0000000000005963 |