Abstract 16117: Critical Role of ADAMTS-4 in the Development of Sporadic Thoracic and Abdominal Aortic Aneurysm and Dissection
Introduction: ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) levels are increased in human descending thoracic aortic aneurysm and dissection (dTAAD) samples.
Hypothesis: We hypothesize that ADAMTS-4 expression is increased in human sporadic ascending thoracic AAD (aTAAD) and abdominal aortic aneurysm (AAA) samples and contributes to aortic aneurysm and dissection (AAD) development in mice.
Method: We examined ADAMTS-4 expression in human aTAAD (n=10, aneurysm without dissection; n=10, dissection) and AAA (n=8) samples. In a sporadic AAD model, we compared AAD formation, aortic destruction, apoptosis and inflammatory cell infiltration in male C57BL/6 wild-type (WT; n=50) and Adamts-4-/- (n=24) mice challenged with high-fat diet and angiotensin II.. We studied the role of ADAMTS-4 in macrophage invasion (transwell assay) and in smooth muscle cell (SMC) apoptosis.
Results: In aTAAD and AAA patient samples, we found significant ADAMTS-4 expression, which was associated with versican degradation. Challenging WT mice induced significant AAD development and ADAMTS-4 expression, particularly in SMCs and macrophages. Adamts-4-/- mice showed significantly reduced challenge-induced aortic destruction, diameter enlargement in all aortic segments as well as AAD formation in ascending (P=0.0003), descending (P=0.05), and suprarenal regions (P=0.047) vs WT mice. Aortas in Adamts-4-/- mice showed reduced versican degradation, macrophage invasion and infiltration, and apoptosis. In cultured SMCs, palmitic acid (PA), which mimics metabolic stress, significantly increased ADAMTS-4 expression and apoptosis. ADAMTS-4 was detected mainly in the cytoplasm of healthy cells but translocated to the nuclei in PA-treated SMCs, especially in apoptotic SMCs. In nuclei, ADAMTS-4 colocalized with, bound, and directly cleaved/degraded poly ADP ribose polymerase-1 (key molecule in DNA repair and cell survival), leading to SMC apoptosis.
Conclusions: ADAMTS contributes to sporadic thoracic and abdominal AAD development by degrading veriscan, promoting inflammatory cell infiltration, and inducing SMC apoptosis and may be a pharmacologic target for inhibiting aortic destruction and AAD progression.
Author Disclosures: P. Ren: None. M. Hughes: None. S. Krishnamoorthy: None. S. Zou: None. Y. Zheng: None. J. Curci: None. J. Coselli: None. S. LeMaire: None. H. Shen: None.
- © 2016 by American Heart Association, Inc.