Cardiac autophagy is a maladaptive response to hemodynamic stress.
Cardiac hypertrophy is a major predictor of heart failure and a prevalent disorder with high mortality. Little is known, however, regarding mechanisms governing the transition from stable cardiac hypertrophy to decompensated heart failure. Here, we tested the role of autophagy, a conserved pathway mediating bulk degradation of long-lived proteins and cellular organelles that can lead to cell death. To quantify autophagic activity, we engineered a line of "autophagy reporter" mice and confirmed that cardiomyocyte autophagy can be induced by short-term nutrient deprivation in vivo. Pressure overload induced by aortic banding induced heart failure and greatly increased cardiac autophagy. Load-induced autophagic activity peaked at 48 hours and remained significantly elevated for at least 3 weeks. In addition, autophagic activity was not spatially homogeneous but rather was seen at particularly high levels in basal septum. Heterozygous disruption of the gene coding for Beclin 1, a protein required for early autophagosome formation, decreased cardiomyocyte autophagy and diminished pathological remodeling induced by severe pressure stress. Conversely, Beclin 1 overexpression heightened autophagic activity and accentuated pathological remodeling. Taken together, these findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.
Zhu
Hongxin
H
Department of Internal Medicine and Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
Tannous
Paul
P
Johnstone
Janet L
JL
Kong
Yongli
Y
Shelton
John M
JM
Richardson
James A
JA
Le
Vien
V
Levine
Beth
B
Rothermel
Beverly A
BA
Hill
Joseph A
JA
D000220:Adaptation, Biological; D000821:Animal Feed; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000601:surgery; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1; D015415:Biomarkers; D002460:Cell Line; D006331:Heart Diseases / Q000473:pathology*; D006579:Heterozygote; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D015415:Biomarkers; D011506:Proteins