Abstract 3015: Matrix Metalloproteinase Inhibition In Rat Abdominal Aortic Aneurysm

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 44; no. Suppl_1; p. A3015
• Main Authors: Zaghloul, Mohamed, Elizondo-Benedetto, Santiago, Arif, Batool, Heo, Gyu Seong, Luehmann, Hannah, Liu, Yongjian, Gropler, Robert J, Sadeghi, Mehran M, Zayed, Mohamed A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.05.2024
• Subjects: Targeted therapeutics; Inflammation; Abdominal aortic aneurysm
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/atvb.44.suppl_1.3015

Background: Matrix metalloproteinases (MMPs) have a robust proteolytic activity and play a fundamental role in degradation of extracellular matrix proteins. This degradation is a hallmark of the initiation, progression, and rupture of abdominal aortic aneurysms (AAAs). Hypothesis: We hypothesized that broad inhibition of MMPs with a 3rd generation MMP inhibitor (GM6001) can reduce AAA inflammation and rupture using an established rat model. Aims: Our study aimed to investigate the potential of GM6001 in reducing AAA-related inflammation using a rat model, filling a critical gap in AAA research. Methods: Male Sprague-Dawley rats underwent intraluminal infrarenal perfusion of abdominal aorta using porcine pancreatic elastase (PPE), and daily β-aminopropionitrile (BAPN) to promote AAA rupture. Starting on postoperative day 3 (POD3) rats were treated daily either with or without GM6001 via intraperitoneal injections. On POD6, treated and untreated groups, underwent PET/CT imaging using a pan-MMP radiotracer 64Cu-RYM2 and in vivo aortic diameter measurement using ultrasound. Rate of rupture of treated and untreated groups was observed until POD14 (Fig 1A). Results: Treated rats demonstrated no evidence of toxicity or weight loss. Compared to untreated rats, treated rats had lower AAA rupture rates (P<0.01; Fig 1B), smaller AAA diameters (P<0.05; Fig 1C), and lower AAA MMP radiotracer uptake (P<0.05; Fig 1D,1G). Total and active MMP-9 were significantly lower in treated rats (Fig 1E-F). In addition, IL-1B, IL-17A, IL-18, IFN-y, and RANTAS were significantly lower in treated rats, but TNF-a was higher (Fig 1H-M). VVG staining demonstrated a higher content of preserved elastin in treated rats (Fig 1N). Conclusion: Inhibition of MMPs with a 3rd generation MMP inhibitor appears to be a promising therapeutic approach to impede the progression, inflammation, and rupture of AAAs in rats. This may represent a renewed pathway for MMP inhibition in human subjects with AAAs.