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Sci Signal. 2017 Feb 28;10(468). pii: eaaf5967. doi: 10.1126/scisignal.aaf5967.

DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress.

Author information

1
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
2
Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
3
Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
4
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. sdas@partners.org.

Abstract

Physiological cardiac hypertrophy, in response to stimuli such as exercise, is considered adaptive and beneficial. In contrast, pathological cardiac hypertrophy that arises in response to pathological stimuli such as unrestrained high blood pressure and oxidative or metabolic stress is maladaptive and may precede heart failure. We found that the transcript encoding DNA damage-inducible transcript 4-like (DDiT4L) was expressed in murine models of pathological cardiac hypertrophy but not in those of physiological cardiac hypertrophy. In cardiomyocytes, DDiT4L localized to early endosomes and promoted stress-induced autophagy through a process involving mechanistic target of rapamycin complex 1 (mTORC1). Exposing cardiomyocytes to various types of pathological stress increased the abundance of DDiT4L, which inhibited mTORC1 but activated mTORC2 signaling. Mice with conditional cardiac-specific overexpression of DDiT4L had mild systolic dysfunction, increased baseline autophagy, reduced mTORC1 activity, and increased mTORC2 activity, all of which were reversed by suppression of transgene expression. Genetic suppression of autophagy also reversed cardiac dysfunction in these mice. Our data showed that DDiT4L may be an important transducer of pathological stress to autophagy through mTOR signaling in the heart and that DDiT4L could be therapeutically targeted in cardiovascular diseases in which autophagy and mTOR signaling play a major role.

PMID:
28246202
PMCID:
PMC5509050
DOI:
10.1126/scisignal.aaf5967
[Indexed for MEDLINE]
Free PMC Article

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