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

Autor: Di Gregoli K; Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK., Atkinson G; Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK., Williams H; Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK., George SJ; Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK., Johnson JL; Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2024 May 27; Vol. 25 (11). Date of Electronic Publication: 2024 May 27.
DOI: 10.3390/ijms25115809
Abstrakt: 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 development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe -/- mice from Ang II-induced AAA formation and rupture-related death, associated with diminished 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 pharmacological 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.
Databáze: MEDLINE
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