Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice.

Autor: Amor M; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Bianco V; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Buerger M; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Lechleitner M; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Vujić N; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Dobrijević A; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria.; Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Akhmetshina A; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Pirchheim A; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Schwarz B; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria., Pessentheiner AR; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria.; Institute for Molecular Biosciences, University of Graz, Graz, Austria., Baumgartner F; Institute of Biomechanics, Graz University of Technology, Graz, Austria., Rampitsch K; Institute of Biomechanics, Graz University of Technology, Graz, Austria., Schauer S; Diagnostics and Research Institute of Pathology, Medical University of Graz, Graz, Austria., Klobučar I; Sisters of Charity, University Hospital Centre, Zagreb, Croatia., Degoricija V; University of Zagreb School of Medicine, Zagreb, Croatia.; Department of Medicine, Sisters of Charity, University Hospital Centre, Zagreb, Croatia., Pregartner G; Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria., Kummer D; Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria., Svecla M; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy., Sommer G; Institute of Biomechanics, Graz University of Technology, Graz, Austria.; BioTechMed-Graz, Graz, Austria., Kolb D; Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.; Core Facility Ultrastructural Analysis, Medical University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria., Holzapfel GA; Institute of Biomechanics, Graz University of Technology, Graz, Austria.; BioTechMed-Graz, Graz, Austria.; Department of Structural Engineering, Norwegian University of Science and Technology, Trondheim, Norway., Hoefler G; Diagnostics and Research Institute of Pathology, Medical University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria., Frank S; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria.; BioTechMed-Graz, Graz, Austria., Norata GD; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy., Kratky D; Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, Graz, 8010, Austria. dagmar.kratky@medunigraz.at.; BioTechMed-Graz, Graz, Austria. dagmar.kratky@medunigraz.at.
Jazyk: angličtina
Zdroj: Cardiovascular diabetology [Cardiovasc Diabetol] 2023 Nov 28; Vol. 22 (1), pp. 327. Date of Electronic Publication: 2023 Nov 28.
DOI: 10.1186/s12933-023-02064-3
Abstrakt: Background: Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.
Methods: We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16-20 weeks.
Results: DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs.
Conclusion: We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.
(© 2023. The Author(s).)
Databáze: MEDLINE
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