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. |
---|---|
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.) |
References: | Ann Intern Med. 1997 Mar 15;126(6):441-9. (PMID: 9072929) Heart. 2014 Oct;100(19):1498-505. (PMID: 25060754) Circulation. 2008 Apr 8;117(14):1883-9. (PMID: 18391122) Nat Commun. 2018 Nov 27;9(1):5022. (PMID: 30479344) Ann Vasc Dis. 2018 Mar 25;11(1):84-90. (PMID: 29682112) Circulation. 2015 Aug 18;132(7):578-85. (PMID: 26085454) Front Pharmacol. 2019 Oct 29;10:1242. (PMID: 31736752) JAMA. 2020 May 26;323(20):2029-2038. (PMID: 32453369) J Vis Exp. 2015 Sep 28;(103):. (PMID: 26436287) Curr Med Res Opin. 2004 Apr;20(4):419-32. (PMID: 15119978) Ann Surg. 2022 Sep 1;276(3):511-521. (PMID: 35762613) Arterioscler Thromb Vasc Biol. 2018 Feb;38(2):292-303. (PMID: 29301789) Immunity. 2019 Aug 20;51(2):258-271.e5. (PMID: 31350176) Virulence. 2010 Sep-Oct;1(5):418-22. (PMID: 21178482) Vascul Pharmacol. 2019 May;116:45-50. (PMID: 30946986) Hypertension. 2015 Apr;65(4):800-5. (PMID: 25691624) Nat Commun. 2019 Nov 6;10(1):5046. (PMID: 31695038) Prog Mol Biol Transl Sci. 2017;147:1-73. (PMID: 28413025) Methods Mol Biol. 2018;1784:263-275. (PMID: 29761406) J Clin Invest. 2019 May 20;129(7):2619-2628. (PMID: 31107246) Arterioscler Thromb Vasc Biol. 2015 Feb;35(2):378-88. (PMID: 25524776) Curr Opin Cardiol. 2015 Nov;30(6):566-73. (PMID: 26352243) Methods Mol Biol. 2010;622:271-7. (PMID: 20135289) Arterioscler Thromb Vasc Biol. 2019 Apr;39(4):623-634. (PMID: 30760015) Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1753-7. (PMID: 27470509) Nat Rev Cardiol. 2017 Aug;14(8):457-471. (PMID: 28406184) Nat Rev Cardiol. 2020 Apr;17(4):216-228. (PMID: 31578516) Biomolecules. 2022 Oct 21;12(10):. (PMID: 36291750) Dis Model Mech. 2016 May 1;9(5):541-52. (PMID: 26989193) Blood. 2009 Oct 8;114(15):3244-54. (PMID: 19567879) Nature. 2012 Aug 16;488(7411):404-8. (PMID: 22842901) Br J Pharmacol. 2015 Jun;172(11):2769-81. (PMID: 25631332) Microvasc Res. 2022 Sep;143:104398. (PMID: 35671836) ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6. (PMID: 24900432) FEBS Open Bio. 2019 Jun;9(6):1137-1143. (PMID: 31001930) Nat Immunol. 2015 Jan;16(1):67-74. (PMID: 25419628) J Immunol. 2019 Mar 15;202(6):1777-1785. (PMID: 30710046) Arterioscler Thromb Vasc Biol. 2022 Aug;42(8):1060-1076. (PMID: 35510553) Circ Res. 2015 Nov 6;117(11):e80-9. (PMID: 26443597) JCI Insight. 2020 Sep 3;5(17):. (PMID: 32879137) PLoS One. 2016 Jun 13;11(6):e0157265. (PMID: 27295295) Ann N Y Acad Sci. 1999 Jun 30;878:179-90. (PMID: 10415729) J Clin Invest. 2002 Sep;110(5):625-32. (PMID: 12208863) J Cardiol. 2021 May;77(5):471-474. (PMID: 33148468) J Surg Res. 2012 Jul;176(1):321-8. (PMID: 21764069) Atherosclerosis. 2018 Apr;271:182-192. (PMID: 29524861) Ann Vasc Surg. 2014 Jan;28(1):87-92. (PMID: 24189004) Am Heart J. 2019 Nov;217:72-83. (PMID: 31520897) J Exp Med. 2021 Jun 7;218(6):. (PMID: 33779682) Nat Rev Cardiol. 2011 Feb;8(2):92-102. (PMID: 21079638) J Vasc Res. 2008;45(2):143-52. (PMID: 17957103) Front Physiol. 2020 Feb 05;11:54. (PMID: 32116765) Clin Epigenetics. 2016 Jan 13;8:3. (PMID: 26767057) PLoS Pathog. 2015 Dec 28;11(12):e1005338. (PMID: 26709698) Transgenic Res. 1999 Aug;8(4):265-77. (PMID: 10621974) Molecules. 2015 Mar 02;20(3):3898-941. (PMID: 25738536) J Surg Res. 2012 Dec;178(2):1038-45. (PMID: 22651981) N Engl J Med. 2014 Nov 27;371(22):2101-8. (PMID: 25427112) JCI Insight. 2021 Jun 22;6(12):. (PMID: 34003795) Antioxid Redox Signal. 2016 Nov 10;25(14):758-774. (PMID: 26983461) JAMA Surg. 2015 Jan;150(1):44-50. (PMID: 25389641) Life Sci. 2020 Jul 15;253:117659. (PMID: 32283055) Immunol Cell Biol. 2015 Mar;93(3):226-32. (PMID: 25666097) |
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: 20240902 |
رمز التحديث: | 20240902 |
مُعرف محوري في PubMed: | PMC10526639 |
DOI: | 10.1097/SLA.0000000000005963 |
PMID: | 37325923 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1528-1140 |
---|---|
DOI: | 10.1097/SLA.0000000000005963 |