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Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice.
Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice. Scientific reports Ren, P. n., Hughes, M. n., Krishnamoorthy, S. n., Zou, S. n., Zhang, L. n., Wu, D. n., Zhang, C. n., Curci, J. A., Coselli, J. S., Milewicz, D. M., LeMaire, S. A., Shen, Y. H. 2017; 7 (1): 12351Abstract
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.
View details for DOI 10.1038/s41598-017-12248-z
View details for PubMedID 28955046
View details for PubMedCentralID PMC5617887