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Published on: September 28, 2015
Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms
Karina Di Gregoli1, Georgia Atkinson1, Helen Williams1
1Laboratory of Cardiovascular Pathology, Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK.
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 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.
Insights
Pharmacological inhibition of matrix metalloproteinase-12 (MMP-12) protects against abdominal aortic aneurysm (AAA) formation and progression in mice. This MMP-12 inhibitor therapy improves survival and offers potential for human AAA treatment.
Area of Science:
- Cardiovascular Biology
- Vascular Biology
- Pharmacology
Background:
- Abdominal aortic aneurysms (AAAs) involve matrix metalloproteinase (MMP) activity, macrophage infiltration, and elastin degradation.
- MMP-12's role in AAA development is debated, with conflicting results from genetic studies.
- Atherosclerosis often coexists with AAAs, complicating understanding of disease mechanisms.
Purpose of the Study:
- To investigate the protective effects of a novel MMP-12 phosphinic peptide inhibitor (RXP470.1) against AAA formation and progression.
- To assess the impact of MMP-12 inhibition on aortic remodeling, extracellular matrix integrity, and inflammatory pathways in a mouse model.
- To evaluate RXP470.1 in a human ex vivo model of early aneurysm development.
Main Methods:
- Utilized angiotensin II-infused Apoe-/- mice, a model for hypercholesterolemia and AAA development.
- Administered RXP470.1, a specific MMP-12 inhibitor, to assess its therapeutic efficacy.
- Performed proteomic analyses to evaluate changes in extracellular matrix remodeling and inflammatory markers.
- Included complementary studies using a human ex vivo model of early aneurysm formation.
Main Results:
- RXP470.1 administration significantly protected against Ang II-induced AAA formation and reduced rupture-related mortality in hypercholesterolemic mice.
- MMP-12 inhibition led to reduced medial thinning and elastin fragmentation, with increased collagen deposition in the aorta.
- Proteomic analysis confirmed that RXP470.1 favorably modulated extracellular matrix proteins and inflammatory pathways.
- Treatment of established AAAs with RXP470.1 suppressed aortic dilation, rupture, medial thinning, and elastin destruction.
Conclusions:
- Pharmacological inhibition of MMP-12 activity effectively retards AAA progression and enhances survival in a murine model.
- These findings provide proof-of-concept for MMP-12 inhibitor therapy in managing human abdominal aortic aneurysms.
- Targeting MMP-12 represents a promising therapeutic strategy for AAA treatment, warranting further translational research.
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