Abstract 315: SmgGDS Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells

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 +/- 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 Apoe -/- SmgGDS +/- mice compared with Apoe -/- mice, whereas that of the abdominal aorta remained comparable between the two genotypes. Histological analysis of Apoe -/- SmgGDS +/- 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, Apoe -/- SmgGDS +/- 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, Apoe -/- SmgGDS +/- 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, expressions of FBN1 , ACTA2 , MYH11 , MLK and PRKG1 , which are force generation genes, were significantly reduced in Apoe -/- SmgGDS +/- 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 in Apoe -/- SmgGDS +/- mice. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.