Am J Physiol Cell Physiol 2010,
Song, Xiaoxiao; Kusakari, Yoichiro; Xiao, Chun-Yang; Kinsella, Stuart D; Rosenberg, Michael A; Scherrer-Crosbie, Marielle; Hara, Kenta; Rosenzweig, Anthony; Matsui, Takashi
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)-1β 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-κB-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.
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Text Mining Data
IL-6 ⊣ mTOR: " mTOR
LPS induced secretion of IL-6
( P < 0.001 ), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR "
IL-6 → 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 "
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