mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy
mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy
复制标题
DOI：
10.1152/ajpcell.00338.2010
复制
发表时间：
2010-12-01
影响因子：
5.5
通讯作者：
Matsui, Takashi
中科院分区：
文献类型：
--
作者：
Song, Xiaoxiao;Kusakari, Yoichiro;Matsui, Takashi
[10]张晓，张晓，张晓. mTOR减弱心肌细胞中的炎症反应并防止病理性肥大中的心功能障碍。美国生理学杂志细胞生理学299：C1256-C1266，2010年。首次发表于2010年9月22日; doi：10.1152/ajpcell.00338.2010。先前的研究表明，雷帕霉素抑制哺乳动物雷帕霉素靶蛋白（mTOR）可抑制心肌肥大。然而，mTOR在病理性肥大的心功能不全进展中的作用尚未完全确定。有趣的是，最近的报道表明，在心力衰竭的发展中起重要作用的炎症反应在某些条件下被雷帕霉素增强。本研究的目的是确定mTOR对病理性肥大的影响，并评估心脏mTOR是否调节炎症反应。我们产生了心脏特异性过表达野生型mTOR（mTOR-Tg）的转基因小鼠。mTOR-Tg小鼠在由横向主动脉缩窄（TAC）诱导的左心室压力超负荷后免受心功能障碍（P < 0.01），并且在TAC后4周与同窝对照（WT）相比具有显著更少的间质纤维化（P < 0.01）。相反，TAC引起WT的心功能不全。在TAC后1周，WT小鼠的促炎细胞因子白细胞介素（IL）-1 β和IL-6显著增加，但在mTOR-Tg小鼠中没有。为了进一步表征mTOR激活的作用，我们将转染mTOR的HL-1心肌细胞暴露于脂多糖（LPS）。mTOR过表达抑制LPS诱导的IL-6分泌（P < 0.001），mTOR抑制剂雷帕霉素和PP 242可消除mTOR的这种抑制作用。此外，mTOR过表达减少了HL-1细胞中NF-κ B调节的转录。这些数据表明，mTOR减轻压力超负荷的不良后果，并且mTOR的这种心脏保护作用是通过调节炎症反应介导的。
Song X, Kusakari Y, Xiao C, Kinsella SD, Rosenberg MA, Scherrer-Crosbie M, Hara K, Rosenzweig A, Matsui T. mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol 299: C1256-C1266, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00338.2010.-Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1 beta and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-kappa B-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction.