title: DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress.
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 ofDDiT4L, 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.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Bridget
authors.identifier: 0000-0002-3190-4796
authors.initials: B
authors.lastname: Simonson
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Vinita
authors.initials: V
authors.lastname: Subramanya
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Mun Chun
authors.initials: MC
authors.lastname: Chan
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Aifeng
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Hannabeth
authors.initials: H
authors.lastname: Franchino
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Filomena
authors.identifier: 0000-0003-1540-7447
authors.initials: F
authors.lastname: Ottaviano
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Knight
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Danielle
authors.identifier: 0000-0002-3557-4915
authors.initials: D
authors.lastname: Hunt
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Ionita
authors.identifier: 0000-0001-6655-3298
authors.initials: I
authors.lastname: Ghiran
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.affiliation: Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kontaridis
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. sdas@partners.org.|Cardiovascular Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Saumya
authors.identifier: 0000-0002-4521-4606
authors.initials: S
authors.lastname: Das
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2