Journal Article

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

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

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/2 / 13/51 / 13/89 / 14/19 / 14/63 / 631/80/82/23 / 64/60 / 692/699/75/593/1301 / 82/51 / 82/80 / ADAMTS4 Protein - genetics / ADAMTS4 Protein - metabolism / Adenosine diphosphate / Aged / Aneurysm, Dissecting - etiology / Aneurysm, Dissecting - pathology / Aneurysms / Angiotensin / Angiotensin II / Angiotensin II - administration & dosage / Angiotensin II - adverse effects / Animals / Aorta - pathology / Aortic Aneurysm, Thoracic - etiology / Aortic Aneurysm, Thoracic - pathology / Aortic Aneurysm, Thoracic - surgery / Aortic aneurysms / Apoptosis / Cell survival / Diet, High-Fat - adverse effects / Disease Models, Animal / DNA repair / Female / High fat diet / Humanities and Social Sciences / Humans / Infiltration / Inflammation / Macrophages / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Middle Aged / multidisciplinary / Myocytes, Smooth Muscle - pathology / Nuclei / Proteinase / Proteolysis / Ribose / Science / Science (multidisciplinary) / Smooth muscle / Thorax / Thrombospondin / Vascular diseases / Versican / Versicans - metabolism