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Supplemental Digital Content is available in the text. Background: Thoracic aortic aneurysm (TAA) and dissection are fatal diseases that 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 aortic smooth muscle cells (AoSMCs) causes TAA and thoracic aortic dissection. Methods: To examine the role of SmgGDS in TAA formation, we used an angiotensin II (1000 ng·min−1·kg−1, 4 weeks)–induced TAA model. Results: We found that 33% of Apoe −/− SmgGDS +/− mice died suddenly as a result of TAA rupture, whereas there was no TAA rupture in Apoe −/− control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the 2 genotypes. We performed ultrasound imaging every week to follow up 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 2 genotypes. Histological analysis of Apoe −/− SmgGDS +/− mice showed dissections of major thoracic aorta in the early phase of angiotensin II infusion (day 3 to 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 angiotensin II (100 nmol/L) treatment for 24 hours, Apoe −/− SmgGDS +/− AoSMCs showed significantly increased matrix metalloproteinase activity and oxidative stress levels compared with Apoe−/− AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of fibrillin-1 (FBN1), α-smooth muscle actin (ACTA2), myosin-11 (MYH11), MYLLK , and PRKG1 , which are force generation genes, were significantly reduced in Apoe −/− SmgGDS +/− AoSMCs compared with Apoe−/− AoSMCs. A similar tendency was noted in AoSMCs from patients with TAA compared with those from control subjects. 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. [ABSTRACT FROM AUTHOR]

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]