RRC ID 28124
Author Hariharan N, Ikeda Y, Hong C, Alcendor RR, Usui S, Gao S, Maejima Y, Sadoshima J.
Title Autophagy plays an essential role in mediating regression of hypertrophy during unloading of the heart.
Journal PLoS One
Abstract Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading. Mice were subjected to transverse aortic constriction (TAC) for 1 week, after which the constriction was removed (DeTAC). Regression of cardiac hypertrophy was observed after DeTAC, as indicated by reduction of LVW/BW and cardiomyocyte cross-sectional area. Indicators of autophagy, including LC3-II expression, p62 degradation and GFP-LC3 dots/cell, were significantly increased after DeTAC, suggesting that autophagy is induced. Stimulation of autophagy during DeTAC was accompanied by upregulation of FoxO1. Upregulation of FoxO1 and autophagy was also observed in vitro when cultured cardiomyocytes were subjected to mechanical stretch followed by incubation without stretch (de-stretch). Transgenic mice with cardiac-specific overexpression of FoxO1 exhibited smaller hearts and upregulation of autophagy. Overexpression of FoxO1 in cultured cardiomyocytes significantly reduced cell size, an effect which was attenuated when autophagy was inhibited. To further examine the role of autophagy and FoxO1 in mediating the regression of cardiac hypertrophy, beclin1+/- mice and cultured cardiomyocytes transduced with adenoviruses harboring shRNA-beclin1 or shRNA-FoxO1 were subjected to TAC/stretch followed by DeTAC/de-stretch. Regression of cardiac hypertrophy achieved after DeTAC/de-stretch was significantly attenuated when autophagy was suppressed through downregulation of beclin1 or FoxO1. These results suggest that autophagy and FoxO1 play an essential role in mediating regression of cardiac hypertrophy during mechanical unloading.
Volume 8(1)
Pages e51632
Published 2013-1-1
DOI 10.1371/journal.pone.0051632
PII PONE-D-12-20266
PMID 23308102
PMC PMC3538681
MeSH Animals Autophagy* / drug effects Cardiomegaly / genetics Cardiomegaly / metabolism Cardiomegaly / pathology Cardiomegaly / physiopathology* Cell Size Cells, Cultured Forkhead Box Protein O1 Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism Heart / physiopathology* Mice Mice, Inbred C57BL Mice, Knockout Myocardium / metabolism Myocardium / pathology Myocytes, Cardiac / metabolism Myocytes, Cardiac / pathology Rats Up-Regulation Weight-Bearing
IF 2.74
Times Cited 52
Mice RBRC00806