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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2023

Open Access 01-12-2023 | Insulins | Research

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

Authors: Melina Amor, Valentina Bianco, Martin Buerger, Margarete Lechleitner, Nemanja Vujić, Anja Dobrijević, Alena Akhmetshina, Anita Pirchheim, Birgit Schwarz, Ariane R. Pessentheiner, Franziska Baumgartner, Katharina Rampitsch, Silvia Schauer, Iva Klobučar, Vesna Degoricija, Gudrun Pregartner, Daniel Kummer, Monika Svecla, Gerhard Sommer, Dagmar Kolb, Gerhard A. Holzapfel, Gerald Hoefler, Saša Frank, Giuseppe Danilo Norata, Dagmar Kratky

Published in: Cardiovascular Diabetology | Issue 1/2023

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Abstract

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.
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Metadata
Title
Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice
Authors
Melina Amor
Valentina Bianco
Martin Buerger
Margarete Lechleitner
Nemanja Vujić
Anja Dobrijević
Alena Akhmetshina
Anita Pirchheim
Birgit Schwarz
Ariane R. Pessentheiner
Franziska Baumgartner
Katharina Rampitsch
Silvia Schauer
Iva Klobučar
Vesna Degoricija
Gudrun Pregartner
Daniel Kummer
Monika Svecla
Gerhard Sommer
Dagmar Kolb
Gerhard A. Holzapfel
Gerald Hoefler
Saša Frank
Giuseppe Danilo Norata
Dagmar Kratky
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-023-02064-3

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