Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

Karina Di Gregoli*, Georgia G Atkinson*, Helen Williams*, Sarah J George*, Jason L Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor, protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe-/- mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm develop-ment. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Ap-oe-/- mice from Ang II-induced AAA formation and rupture-related death, associated with di-minished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that phar-macological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
Original languageEnglish
Article number5809
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume25
Issue number11
DOIs
Publication statusPublished - 27 May 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • abdominal aortic aneurysm
  • Matrix metalloproteases (MMPs)
  • proteomics
  • macrophage
  • pharmacology

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