P. Ren1,2, M. Hughes1,2, L. Zhang1,2, Y. Zheng1,2, S. Krishnamoorthy1,2, J. Coselli1,2,3, Y. Shen1,2,3, S. LeMaire1,2,3 1Baylor College of Medicine,Cardiothoracic Surgery,Houston, TEXAS, USA 2Texas Heart Institute,Cardiovascular Surgery,Houston, TEXAS, USA 3Baylor College of Medicine,Cardiovascular Research Institute,Houston, TEXAS, USA
Introduction: We have previously shown that ADAMTS-4, a disintegrin and metalloproteinase with thrombospondin motifs 4, was significantly elevated in aortic tissue from patients with aortic aneurysms and dissections (AAD), and that ADAMTS-4 contributed to aortic destruction and sporadic AAD development in a mouse model. The current study aimed to determine whether pharmacologic inhibition of ADAMTS-4 can prevent AAD development in mice.
Methods: Four-week old male wild type C57BL/6J mice (n=83) were challenged with high-fat diet for 8 weeks and received angiotensin II infusion during the last 4 weeks. The challenged mice were randomly assigned to receive water (control group, n=50) or 75mg/kg/day of ADAMTS inhibitor pentosan polysulfate sodium (NaPPS) (treatment group, n=33). Incidence of AAD was evaluated by two independent observers. Aortic inflammatory cell infiltrate, ECM destruction, SMC apoptosis, and ADAMTS-4 levels were measured.
Results: NaPPS treatment reduced the development of AAD. The overall incidence of AAD decreased from 78% in the control group to 58% in the NaPPS treatment group (P=0.05). AAD reduction was particularly significant in the descending aorta (36% in control group vs 15% in NaPPS treatment group [P=0.05]) and in the suprarenal aorta (60% in control group vs 33% in NaPPS treatment group [P=0.03]). Furthermore, aortas from the NaPPS treatment group showed greater reductions in ADAMTS-4 expression, macrophage infiltration, elastic fiber destruction and SMC apoptosis as compared to controls.
Conclusion: ADAMTS inhibitor NaPPS partially reduced the challenge-induced aortic destruction, inflammation, and the development of AAD in mice. Thus, pharmacologically targeting ADAMTS-4 may be a promising therapeutic strategy for preventing AAD formation and progression.