Rapamycin prevents thoracic aortic aneurysm and dissection in mice
Biao Zhou, Wei Li, Guizhen Zhao, Bing Yu, Baihui Ma, Zhujiang Liu, Nan Xie, Yi Fu, Ze Gong, Rongbo Dai, Xiaoming Zhang, Wei KongJournal of Vascular Surgery2018
Objective: The purpose of this study was to investigate whether rapamycin inhibits the development of thoracic aortic aneurysm and dissection (TAAD) in mice. Methods: Three-week-old C57BL/6J male mice were fed a normal diet and randomized into a control group (n = 6), β-aminopropionitrile fumarate (BAPN) group (Gp A; n = 15), BAPN plus rapamycin (5 mg) group (Gp B; n = 8), and BAPN plus rapamycin (10 mg) group (Gp C; n = 8). Gp A, Gp B, and Gp C were administered BAPN (1 g/kg/d) for 4 weeks. One week after BAPN administration, Gp B and Gp C were treated with rapamycin (5 mg/kg/d or 10 mg/kg/d) through gavage for 21 days. Thoracic aortas were harvested for Western blot and immunofluorescence staining at day 14 and for morphologic and histologic analyses at day 28. Results: BAPN treatment induced TAAD formation in mice. The incidence of TAAD in control, Gp A, Gp B, and Gp C mice was 0%, 80%, 25%, and 37.5%, respectively. Smaller thoracic aortic diameters (ascending aorta and arch) were observed in Gp B and Gp C mice than in Gp A mice (Gp B vs Gp A: ascending aorta, ex vivo, 1.07 ± 0.21 mm vs 1.80 ± 0.67 mm [P < .05]; aortic arch, ex vivo, 1.51 ± 0.40 mm vs 2.70 ± 1.06 mm [P < .05]; Gp C vs Gp A: ascending aortas, ex vivo, 1.10 ± 0.33 mm vs 1.80 ± 0.67 mm [P < .05]; aortic arch, ex vivo, 1.55 ± 0.56 mm vs 2.70 ± 1.06 mm [P < .05]). TAAD mice exhibited elastin fragmentation, abundant inflammatory cell infiltration, and significantly increased matrix metalloproteinase production in the aorta, and rapamycin treatment alleviated these changes. The protein levels of p-S6K and p-S6 in TAAD aortic tissues increased significantly, whereas they were suppressed by rapamycin. Conclusions: Rapamycin suppressed TAAD formation, probably by inhibition of mechanistic target of rapamycin signaling and reduction of inflammatory cell infiltration and matrix metalloproteinase 9 production. Targeting of the mechanistic target of rapamycin signaling pathway using rapamycin may be a favorable modulation for the clinical treatment of TAAD. Clinical Relevance: Thoracic aortic aneurysm and dissection (TAAD) remain difficult to manage clinically, and no pharmacologic interventions for TAAD have been properly validated. Our study demonstrated that rapamycin suppressed TAAD formation, probably by inhibition of inflammatory cell infiltration and matrix metalloproteinase production through mechanistic target of rapamycin signaling. A mechanistic target of rapamycin signaling inhibitor may be a clinical treatment target for TAAD.