Gao Xiao-Ming, Wong Geoffrey, Wang Binghui, Kiriazis Helen, Moore Xiao-Lei, Su Yi-Dan, Dart Anthony, Du Xiao-Jun
Experimental Cardiology Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia.
J Hypertens. 2006 Aug;24(8):1663-70. doi: 10.1097/01.hjh.0000239304.01496.83.
Inhibition of established left ventricular hypertrophy (LVH) and fibrosis may bring clinical benefits by reducing cardiac morbidity and mortality. The mammalian target of rapamycin, mTOR, is known to play a critical role in determining cell and organ size. We investigated whether mTOR inhibition can inhibit the chronic pressure-overload-induced LVH and fibrosis.
Male FVB/N mice underwent transverse aortic constriction (TAC) for 5 weeks to allow for establishment of LVH, followed by treatment with the mTOR inhibitor, Rapamune (2 mg/kg per day, gavage), for 4 weeks. Echocardiography was used to monitor changes in LVH and function. Haemodynamic, morphometric, histological and molecular analyses were conducted.
Inhibition of mTOR by Rapamune was confirmed by a suppression of activated phosphorylation of ribosomal S6 protein and eukaryotic translation initiation factor-4E due to pressure overload. Despite a comparable degree of pressure overload between the vehicle- or Rapamune-treated TAC groups, Rapamune treatment for 4 weeks attenuated TAC-induced LVH by 46%, estimated by LV weight or myocyte size, and LV fractional shortening was also preserved versus vehicle-treated control (39 +/- 1 versus 32 +/- 2%, P < 0.05). Inhibition of established LVH by Rapamune was associated with a 38% reduction in collagen content. Moreover, altered gene expression due to pressure overload was largely restored.
Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.
抑制已形成的左心室肥厚（LVH）和纤维化可能通过降低心脏发病率和死亡率带来临床益处。已知雷帕霉素的哺乳动物靶点mTOR在决定细胞和器官大小方面起关键作用。我们研究了mTOR抑制是否能抑制慢性压力超负荷诱导的LVH和纤维化。
雄性FVB/N小鼠接受主动脉缩窄（TAC）5周以建立LVH，随后用mTOR抑制剂雷帕鸣（每天2mg/kg，灌胃）治疗4周。使用超声心动图监测LVH和功能的变化。进行血流动力学、形态学、组织学和分子分析。
雷帕鸣对mTOR的抑制通过压力超负荷导致的核糖体S6蛋白和真核翻译起始因子-4E的活化磷酸化受到抑制得以证实。尽管在给予载体或雷帕鸣治疗的TAC组之间压力超负荷程度相当，但通过LV重量或心肌细胞大小估计，雷帕鸣治疗4周可使TAC诱导的LVH减轻46%，并且与给予载体治疗的对照组相比，LV缩短分数也得以保留（39±1对32±2%，P<0.05）。雷帕鸣对已形成的LVH的抑制与胶原蛋白含量降低38%相关。此外，压力超负荷导致的基因表达改变在很大程度上得以恢复。
尽管存在持续的压力超负荷，但雷帕鸣治疗4周对mTOR的抑制可减轻长期形成的LVH和心脏纤维化，并保留收缩功能。
