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Abstract 10466: SmgGDS Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells.
- Source :
-
Circulation . 2018 Supplement, Vol. 138, pA10466-A10466. 1p. - Publication Year :
- 2018
-
Abstract
- Background: Thoracic aortic aneurysm (TAA) and dissection (TAD) are fatal diseases, which cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in AoSMCs causes TAA and TAD. Methods and Results: To examine the role of SmgGDS in TAA formation, we employed an angiotensin II (AngII, 1,000 ng/min/kg, 4weeks)-induced TAA model in Apoe-/-SmgGDS+/- (DKO)mice, in which 33% died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe-/- control mice. In contrast, there was no significant difference in the ratio of AAA rupture between the two genotypes. We performed ultrasound imaging every week to follow the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in DKO mice compared with Apoe-/- mice, whereas that of the abdominal aorta remained comparable between the two genotypes. Histological analysis of DKO mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5) and more severe elastin degradation compared with Apoe -/- mice. Mechanistically, DKO mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe-/- mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, DKO AoSMCs showed significantly increased MMP activity and oxidative stress levels compared with Apoe-/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, force generation genes were significantly reduced in DKO AoSMCs compared with Apoe-/- AoSMCs. Importantly, RhoA and RhoC activities were significantly decreased in DKO AoSMCs compared with Apoe-/- AoSMCs. Similar tendency was noted in AoSMCs from TAA patients compared with those from controls. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta and prevented TAA rupture in DKO mice. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00097322
- Volume :
- 138
- Database :
- Academic Search Index
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 135764294