Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice

Pingping Ren,Joseph S Coselli,Sili Zou,Darrell Wu,Ying H Shen,Lin Zhang,Dianna M Milewicz,Swapna Krishnamoorthy,Scott A Lemaire,John A Curci,Chen Zhang,Michael Hughes

doi:10.1038/s41598-017-12248-z

Abstract

Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency (Adamts-4−/−) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

Highlights

Matrix proteases, such as matrix metalloproteinases (MMPs)[4], play a critical role in the degradation of aortic ECM and in the formation of aneurysm and dissections (AADs)
We examined the role of ADAMTS-4 in AAD development by comparing AAD formation in challenged wild-type (WT) mice and in challenged ADAMTS-4–deficient (Adamts-4−/−) mice that had no detectable ADAMTS-4 protein (Fig. 1C)
We provide evidence that ADAMTS-4 plays an important role in aortic destruction and AAD formation

Summary

Introduction

Matrix proteases, such as matrix metalloproteinases (MMPs)[4], play a critical role in the degradation of aortic ECM and in the formation of AAD. We have recently reported the increased expression of ADAMTS-4 in aortic tissues from patients with descending thoracic AAD14. It is unclear whether ADAMTS-4 plays a role in AAD development. We assessed the role of ADAMTS-4 in sporadic AAD development in mice, studied its effects on macrophage migration and SMC apoptosis in cultured cells, and examined its expression in aortic tissues from patients with. Our findings show that ADAMTS-4 plays a critical role in sporadic AAD formation by degrading veriscan, promoting inflammatory cell infiltration, and inducing SMC apoptosis. ADAMTS-4 levels were significantly increased in sporadic TAAD

Methods

Results

Conclusion