BioProject

Aortic dissection (AD) is a medical emergency that leads to sudden death. Effective medical therapy is not available because molecular mechanism of AD is poorly understood. More...

Aortic dissection (AD) is a medical emergency that leads to sudden death. Effective medical therapy is not available because molecular mechanism of AD is poorly understood. We performed the transcriptome analysis in mouse AD model that was created by infusion of beta-aminopropionitrile, a collagen crosslink inhibitor, and angiotensin II. Bayesian network analysis of the transcriptome revealed several distinct gene clusters that were tightly co-regulated during AD development. Functional annotation analysis revealed that each gene cluster has distinct function, namely, cell proliferation, inflammation, cell locomotion and adhesion, and muscle differentiation. Among the gene clusters, cell proliferation cluster was the first to be activated during AD development. Cell proliferation before AD development was confirmed by immunoblotting of G1 cyclins. Immunostaining for Ki67 and cell markers revealed the proliferation of smooth muscle cells, fibroblasts, and monocytes in aortic tissue before AD development. Treatment of mice with rapamycin, an mTOR inhibitor, suppressed cell proliferative response in AD model. Rapamycin completely prevented AD when given before AD development, and effectively suppressed progression when given after AD development. Interestingly, transcriptome analysis showed that rapamycin strongly suppressed cell proliferation and muscle differentiation clusters, but its effect on inflammation cluster was modest. We concluded that mTOR constitutes an essential part of the molecular pathogenesis of AD by regulating cell proliferation, and represents a new therapeutic target. Overall design: Aortic dissection model was created by continuous infusion of 150 mg/kg/day beta-aminopropionitrile, a collagen crosslink inhibitor, and 1 ug/kg/min angiotensin II (B+A). Rapamycin (2 mg/kg/day) or dimethylsulfoxide (DMSO, vehicle) was intraperitoneally administored to mice once a day. Four experimental groups were set; DMSO alone (Pre), rapamycin alone, B+A+DMSO, and B+A+rapamycin, each of which contained 3 mice. Aortic samples were obtained at 3 days of experiment. Less...