AMP-activated protein kinase (AMPK) negatively regulates mammalian target of rapamycin (mTOR), the master regulator of translational machinery and cell growth. Recently, we demonstrated that the progressive left ventricular (LV) hypertrophy and heart failure (HF) caused by transverse aortic constriction (TAC) is exacerbated in mice with AMPK12 gene deficiency (AMPK12-/-), and this was associated with increased p- p70S6KThr389, a downstream target of mTOR complex 1 (mTORC1). We also found that activation of AMPK with AICAR or metformin, or overexpression of constitutively active AMPK12, all significantly attenuated cardiac myocyte hypertrophy and p-p70S6KThr389 in vitro. However, the mechanism by which loss of AMPK12 causes increased activation of the mTORC1/p-p70S6k Thr389 signaling pathway after TAC is not clear. DNA-damage-inducible transcript 4 (DDIT4) is a novel stress-responsive gene that negatively regulates the mTORC1 pathway in several tumor-derived cell lines. Although no published studies examining DDIT4 in the heart are available, using global microarray profiling we found that AMPK12-/- mice have decreased expression of myocardial DDIT4. These findings suggest that DDIT4 could provide the essential link by which AMPK12-/- causes activation of the mTORC1 and thereby exacerbates LV hypertrophy during stress conditions. Consequently, studies are proposed to determine whether the novel mTORC1 suppressor DDIT4 is instrumental in attenuating TAC-induced LV hypertrophy and HF in mice after TAC, and the molecular mechanisms by which AMPK12 facilitates adaptation of the heart to hemodynamic overload. Our central hypothesis is that DDIT4 attenuates chronic TAC-induced cardiac myocyte hypertrophy by attenuating the mTORC1 signaling pathway. We also hypothesize that AMPK regulates mTORC1 signaling at least partially through DDIT4. We plan to test our central hypothesis by pursuing the following two Specific Aims: i) Identify the overall impact of DDIT4 on myocardial mTORC1 signaling, LV hypertrophy and HF. Our working hypothesis is that DDIT4 gene deficiency (DDIT4-/-) will amplify activation of the mTOR signaling pathway and LV hypertrophy that occurs when hearts are exposed to systolic overload;ii) Determine the molecular mechanism by which AMPK attenuates mTORC1/p70s6k activation and cardiac myocyte hypertrophy. Our working hypothesis is that DDIT4 plays an essential role for AMPK to attenuate pathological LV hypertrophy. The project is innovative as no previous studies have examined the influence of DDIT4 on LV hypertrophy and HF. Using DDIT4-/- mice combined with TAC will allow us to decipher the role of DDIT4 in attenuating cardiac myocyte hypertrophy under clinically relevant conditions. This project is significant as the knowledge obtained will lead to a better understanding of the molecular mechanisms mediating ventricular hypertrophy and HF, which may provide the basis for developing specific interventions to treat these diseases.
DNA-damage-inducible transcript 4 (DDIT4) is a novel stress-responsive gene that negatively regulate the mTOR pathway in tumor cell lines. However, the effect of DDIT4 on ventricular hypertrophy and dysfunction has not been studied. Using global microarray profiling we recently found that AMPK12 KO mice have decreased expression of myocardial DDIT4, a change may explain the enhanced activation of myocardial mTOR signaling and ventricular hypertrophy in AMPK12 mice in response to chronic stress overload. Studies are proposed to determine whether the novel mTOR suppressor DDIT4 is instrumental in attenuating the development of ventricular hypertrophy and heart failure.
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