Premium
Cell survival effects of an mTOR‐binding protein Tel2 in cardiomyocytes (LB682)
Author(s) -
Yorichika Naaiko,
Matsui Takashi
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb682
Subject(s) - pi3k/akt/mtor pathway , apoptosis , phosphorylation , protein kinase b , programmed cell death , cell growth , mtorc1 , biology , kinase , microbiology and biotechnology , cancer research , genetics
Recent studies including ours suggest that the mechanistic target of rapamycin (mTOR) is sufficient and necessary to prevent cardiomyocyte (CM) cell death against pathological stresses such as myocardial infarction. We also showed that the expression level of mTOR increases in patients and mice with heart failure. However, a mechanism of regulating mTOR expression in the heart remains unknown. Recent reports showed that telomere maintenance 2 (Tel2) interacts with mTOR and regulates its stability and abundance in other tissues. To assess the role of Tel2 in CMs, we examined whether Tel2 is sufficient to stabilize cardiac mTOR and prevent cell death against hypoxic stress. CM cell line HL‐1 cells were transiently overexpressed with Tel2 and then subjected to 24‐hour hypoxia. Cell survival was assessed by morphological changes and Cell Death Detection ELISA (Roche). The necessity of Tel2 was examined by the treatment of CMs with Tel2‐specific siRNA. Western blotting showed overexpression of Tel2 increased the expression level of mTOR by 60% (p<0.05, n=5), and the phosphorylation levels of both S6 (mTORC1 substrate) and Akt (mTORC2 substrate) (90%‐ and 60%‐increase, respectively; p<0.05, n=5). The CMs treated with siRNA targeting Tel2 showed significant decrease in the expression level of mTOR, and the phosphorylation levels of both S6 and Akt compared to controls (p<0.05, n=3). In the hypoxic culture, the round‐shape CMs, indicating cell injury, were less in Tel2‐overexpressed CMs. Cell Death ELISA showed that hypoxia increased apoptosis by 4‐fold compared to baseline controls, whereas Tel2 overexpression suppressed apoptosis by half compared to controls (p<0.05, n=3). These findings suggest that an mTOR‐binding protein Tel2 is sufficient and necessary to protect CMs against hypoxia at least in part by mTOR stabilization. A study of Tel2‐mediated mTOR activation would provide a novel target for a therapy of heart failure following myocardial infarction. Grant Funding Source : Supported by NIH R01 HL098423