Abstract 311: The Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling

Abstract

Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic extracellular matrix (ECM). Evidence is emerging that ECM processing by members of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family could play an important role in the progression of aortic dilatation. In particular, ADAMTS-1 and -4 have been implicated in TAA. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. A model of aortic dilatation by angiotensin II (AngII) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5 Δcat ). Adamts5 Δcat mice showed an attenuated rise in blood pressure whilst displaying increased dilatation of the ascending aorta. Interestingly, a proteomics comparison of the aortic ECM from AngII-treated wildtype and Adamts5 Δcat mice revealed versican as the most up-regulated ECM protein in Adamts5 Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine), an increase in TGFβ and a decrease of low-density lipoprotein-related protein 1 (LRP1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5 , attenuated the generation of versikine but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5 Δcat mice, but was not sufficient to maintain versican processing and prevent aortic dilatation. Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. A compensatory rise in ADAMTS-1 could not prevent aortic dilatation in Adamts5 Δcat mice. LRP1, which has been involved in aneurysm pathology in both human and mice, appears to be linked to ADAMTS-5 and ADAMTS-5-mediated versican cleavage. Further studies are needed to explore the ADAMTS protease family as target for therapeutic approaches aimed to reduce or halt dilatation of the aorta resulting in aneurysm.