Abstract 4143066: C-C Chemokine Receptor Type 2 and Matrix Metalloproteinases Molecular Interaction in Rat Abdominal Aortic Aneurysm

Background: Abdominal aortic aneurysm (AAA) in part results from complex molecular interactions between inflammatory cytokines. C-C chemokine Receptor Type 2 (CCR2) and Matrix Metalloproteinases (MMPs) have fundamental roles in the initiation, progression, and rupture of AAAs. We hypothesized that in a preclinical rodent AAA model CCR2 and MMP molecular interactions are essential for AAA progression and rupture. Aim: Our study aimed to assess the correlation and molecular interaction between CCR2 and MMP in AAAs following pharmacological targeting of each. Methods: Male Sprague-Dawley rats underwent intraluminal infrarenal perfusion of the aorta using porcine pancreatic elastase (PPE), daily β-aminopropionitrile (BAPN) to promote AAA rupture. Starting on postoperative day 3 (POD3), rats were treated with either a MMP inhibitor (MMPi; GM6001) via daily intraperitoneal injection or a CCR2 inhibitor (CCR2i; RS504393) via daily oral gavage. On POD6, the treated and control groups underwent in vivo aortic diameter measurement using ultrasound then their AAA tissues were harvested. The rate of rupture of AAA was observed until POD14 (Fig 1A). Results: CCR2 was directly correlated with total, pro and active MMP9 (r=094, r=0.88, r=0.88, P<0.05 respectively; Fig 1B-D). CCR2i significantly decreased total, pro, and active MMP9; while MMPi significantly reduced CCR2 (Fig 1G-J). Both CCR2i and MMPi significantly decreased AAA diameter and rupture rate (Fig 1E-F). The CCR2i group had significantly lower IL-1β, IL-10, IL-18, and MCP-1 levels compared to the control group (Fig 1K-O). However, MMPi group had significantly lower IFN-γ and higher preserved elastin content compared to the control group (Fig 1Q-S). Both treatment groups had significantly lower IL-17A and higher TNF-α levels (Fig 1M-R). Conclusion: Our study demonstrates a positive correlation between CCR2 and MMP9, suggesting their interdependence in AAA pathogenesis. Furthermore, inhibition of either CCR2 or MMP9 reduced AAA development, highlighting their potential as therapeutic targets. Future studies using CCR2 and MMP9 knockout mice are needed to further elucidate the mechanistic interaction between these molecules in AAA pathogenesis.