Background: The abdominal aortic aneurysm (AAA) is a multifactorial disease with a high prevalence in individuals over 65 years of age, associated with significant mortality and morbidity. There is no specific pharmacological approach that directly targets AAA, and surgery remains the only treatment option. Matrix metalloproteinases (MMPs) constitute a family of enzymes capable of degrading nearly all components of the extracellular matrix (ECM). Among them, the secreted collagenase MMP13 is one of the few enzymes able to cleave the intact triple helix of collagen types I, II, and III. These collagens represent the most abundant structural proteins in the human body and collagenases play a pivotal role in maintaining matrix homeostasis. Owing to its markedly higher enzymatic activity compared to other MMPs, MMP13 is considered substantially more efficient and is thought to be a major contributor to the pathogenesis of AAA, thereby representing a potential therapeutic target. In this study, we explored MMP13 as a potential target for pharmacological inhibition for AAA in mice. Methods: Four groups were established: An untreated wildtype (wt)-group with AAA; a wt-group receiving MMP13 inhibitor injections every second day starting three days before aneurysm induction (prophylactic); a wt-group receiving daily MMP13 inhibitor injections every second day starting three days after aneurysm induction (therapeutic); and a MMP13-/-- group. AAA was induced in wt-mice as wells as in MMP13-/--mice via surgery. The abdominal aorta was ligated, blood flow interrupted and filled with porcine-pancreas-elastase (PPE) for five minutes. Mice were harvested on day 6 after PPE to assess acute inflammation or on day 28 after PPE for tissue remodeling and fibrosis. Ultrasounds were performed to monitor surgery effects, aneurysm induction and growth. Snap-frozen aortas were embedded for histological analysis and stained for collagen, elastin, decorin, a-SMA, MMP activity and CD45/CD68. Results: In both the prophylactic and therapeutic settings, the AAA diameter in mice with 28 days of MMP13-inhibiton was not different from MMP13-/--mice (p=0.289; p=0.877). MMP13-inhibited groups and MMP13-/--mice showed significantly smaller (p=0.039; p=0.009; p=0.007) AAA diameter compared to the control group. In the both settings as well as in MMP13-/--mice, picro sirius staining revealed a higher amount of collagen as well as elastic fibers in aortic tissue when compared to the control group. Likewise, quantification of decorin and a-SMA showed increased levels of these structural proteins in both experimental settings and in MMP13-/--mice relative to the control groups. Also, in both settings as well as in MMP13-/--mice, we could observe less immune cell recruiting and less MMP-activity compared to the control group. Conclusions: MMP13 as a potential target for pharmacological inhibition for AAA in mice shows a significant effect on diameter growth. Also, MMP13 inibition shows similar effectiveness as a knockout of MMP13 gene in mice. Stainings revealed that MMP13-Knockout as well as an inhibition stabilizes the aortic wall in AAA disease and lowers immune cell migration. Nevertheless, the pharmacological inhibition of MMP13 requires thorough characterization.
