Letter abstract
Nature Medicine 13, 619 - 624 (2007)
Published online: 22 April 2007 | doi:10.1038/nm1574
The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress
Atsuko Nakai1,7, Osamu Yamaguchi1,7, Toshihiro Takeda1, Yoshiharu Higuchi1, Shungo Hikoso1, Masayuki Taniike1, Shigemiki Omiya1, Isamu Mizote1, Yasushi Matsumura2, Michio Asahi3, Kazuhiko Nishida1, Masatsugu Hori1, Noboru Mizushima4,5,6 & Kinya Otsu1
Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells1, 2. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy3, 4 and heart failure5, 6, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan
- Department of Medical Information Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan
- Department of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan.
- Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Bunkyoku, Tokyo 113-8613, Japan.
- Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyoku, Tokyo 113-8519, Japan.
- Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honmachi, Kawaguchi, Saitama 332-0012, Japan.
- These authors contributed equally to this work.
Correspondence to: Kinya Otsu1 e-mail: kotsu@medone.med.osaka-u.ac.jp
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