Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis
Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis
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DOI：
10.1097/01.hjh.0000239304.01496.83
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发表时间：
2006-08-01
影响因子：
4.9
通讯作者：
Du, Xiao-Jun
中科院分区：
文献类型：
--
作者：
Gao, Xiao-Ming;Wong, Geoffrey;Du, Xiao-Jun
背景与目的抑制已形成的左心室肥厚（LVH）和纤维化可能通过降低心脏病发病率和死亡率而带来临床益处。雷帕霉素的哺乳动物靶标mTOR已知在决定细胞和器官大小方面起关键作用。我们研究了mTOR抑制是否可以抑制慢性压力超负荷诱导的LVH和fibrosis.Methods雄性FVB/N小鼠进行横向主动脉缩窄（TAC）5周，以建立LVH，然后用mTOR抑制剂Rapamune（2 mg/kg/天，灌胃）治疗4周。超声心动图用于监测LVH和功能的变化。结果Rapamune对mTOR的抑制作用通过抑制压力超负荷引起的核糖体S6蛋白和真核生物翻译起始因子-4E的活化磷酸化来证实。尽管在媒介物或雷帕霉素处理的TAC组之间具有相当程度的压力超负荷，但雷帕霉素处理4周使TAC诱导的LVH减弱46%（通过LV重量或肌细胞大小估计），并且与媒介物处理的对照相比，LV缩短分数也得以保留（39 +/-1对32 +/-2%，P <0.05）。Rapamune对已建立的LVH的抑制与胶原蛋白含量减少38%相关。此外，改变基因表达由于压力超负荷在很大程度上restored.Conclusion尽管持续压力超负荷，抑制mTOR的4周的雷帕霉素治疗减弱慢性建立的左室肥厚和心脏纤维化与保存收缩功能。
Background and objective 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.Methods 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.Results 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.Conclusion 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.