Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells.
Nogi Masamichi,Satoh Kimio,Sunamura Shinichiro,Kikuchi Nobuhiro,Satoh Taijyu,Kurosawa Ryo,Omura Junichi,Elias-Al-Mamun Md,Abdul Hai Siddique Mohammad,Numano Kazuhiko,Kudo Shun,Miyata Satoshi,Akiyama Masatoshi,Kumagai Kiichiro,Kawamoto Shunsuke,Saiki Yoshikatsu,Shimokawa Hiroaki
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·kg, 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.