Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure.
It is still not clear whether loss of cardiomyocytes through programmed cell death causes heart failure. To clarify the role of cell death in heart failure, we generated transgenic mice (TG) that express human diphtheria toxin receptor in the hearts. A mosaic expression pattern of the transgene was observed, and the transgene-expressing cardiomyocytes (17.3% of the total cardiomyocytes) were diffusely scattered throughout the ventricles. Intramuscular injection of diphtheria toxin induced complete elimination of the transgene-expressing cardiomyocytes within 7 days, and approximately 80% of TG showed pathophysiological features characteristic of heart failure and were dead within 14 days. Degenerated cardiomyocytes of the TG heart showed characteristic features indicative of autophagic cell death such as up-regulated lysosomal markers and abundant autophagosomes containing cytosolic organelles like cardiomyocytes of human dilated cardiomyopathy. The heart failure-inducible TG are a useful model for dilated cardiomyopathy, and provided evidence indicating that myocardial cell loss through autophagic cell death plays of a causal role in the pathogenesis heart failure.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Hiroshi
H
Akazawa
Shinji
S
Komazaki
Hiroaki
H
Shimomura
Fumio
F
Terasaki
Yunzeng
Y
Zou
Hiroyuki
H
Takano
Toshio
T
Nagai
Issei
I
Komuro
D000818:Animals; D001343:Autophagy; D015152:Blotting, Northern; D015153:Blotting, Western; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D018076:DNA, Complementary / Q000378:metabolism; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004452:Echocardiography; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology*; D013997:Time Factors; D019076:Transgenes; D015854:Up-Regulation
D018076:DNA, Complementary; D004167:Diphtheria Toxin; D008070:Lipopolysaccharides; D004815:Epidermal Growth Factor