The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress (original) (raw)
- Letter
- Published: 22 April 2007
- Osamu Yamaguchi1 na1,
- 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
Nature Medicine volume 13, pages 619–624 (2007)Cite this article
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Abstract
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.
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References
- Mizushima, N., Ohsumi, Y. & Yoshimori, T. Autophagosome formation in mammalian cells. Cell Struct. Funct. 27, 421–429 (2002).
Article Google Scholar - Levine, B. & Klionsky, D.J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004).
Article CAS Google Scholar - Dammrich, J. & Pfeifer, U. Cardiac hypertrophy in rats after supravalvular aortic constriction. II. Inhibition of cellular autophagy in hypertrophying cardiomyocytes. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 43, 287–307 (1983).
Article CAS Google Scholar - Pfeifer, U., Fohr, J., Wilhelm, W. & Dammrich, J. Short-term inhibition of cardiac cellular autophagy by isoproterenol. J. Mol. Cell. Cardiol. 19, 1179–1184 (1987).
Article CAS Google Scholar - Shimomura, H. et al. Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn. Circ. J. 65, 965–968 (2001).
Article CAS Google Scholar - Miyata, S. et al. Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor. Am. J. Pathol. 168, 386–397 (2006).
Article CAS Google Scholar - Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).
Article CAS Google Scholar - Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
Article CAS Google Scholar - Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Article CAS Google Scholar - Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
Article CAS Google Scholar - Baehrecke, E.H. Autophagy: dual roles in life and death? Nat. Rev. Mol. Cell Biol. 6, 505–510 (2005).
Article CAS Google Scholar - Decker, R.S. & Wildenthal, K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am. J. Pathol. 98, 425–444 (1980).
CAS PubMed PubMed Central Google Scholar - Yan, L. et al. Autophagy in chronically ischemic myocardium. Proc. Natl. Acad. Sci. USA 102, 13807–13812 (2005).
Article CAS Google Scholar - Nishino, I. et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406, 906–910 (2000).
Article CAS Google Scholar - Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, 902–906 (2000).
Article CAS Google Scholar - Sohal, D.S. et al. Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ. Res. 89, 20–25 (2001).
Article CAS Google Scholar - Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).
Article CAS Google Scholar - Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).
Article CAS Google Scholar - Bjorkoy, G. et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
Article Google Scholar - Hosokawa, N., Hara, Y. & Mizushima, N. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett. 580, 2623–2629 (2006).
Article CAS Google Scholar - Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98–103 (2000).
Article CAS Google Scholar - Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell. Biol. 25, 1025–1040 (2005).
Article CAS Google Scholar - Chen, J. et al. Selective requirement of myosin light chain 2v in embryonic heart function. J. Biol. Chem. 273, 1252–1256 (1998).
Article CAS Google Scholar - Yamaguchi, O. et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Invest. 114, 937–943 (2004).
Article CAS Google Scholar - Lyons, G.E. et al. Developmental regulation of myosin gene expression in mouse cardiac muscle. J. Cell Biol. 111, 2427–2436 (1990).
Article CAS Google Scholar - Yamaguchi, O. et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc. Natl. Acad. Sci. USA 100, 15883–15888 (2003).
Article CAS Google Scholar - Wencker, D. et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J. Clin. Invest. 111, 1497–1504 (2003).
Article CAS Google Scholar - Hirotani, S. et al. Involvement of nuclear factor-κB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy. Circulation 105, 509–515 (2002).
Article CAS Google Scholar - Zhou, Y.Y. et al. Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiology. Am. J. Physiol. Heart Circ. Physiol. 279, H429–H436 (2000).
Article CAS Google Scholar - Mizushima, N. et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–668 (2001).
Article CAS Google Scholar
Acknowledgements
We are grateful to K. Chien (Harvard University) for the gift of MLC-2v Cre mice, J. Molkentin (Cincinnati Children's Hospital Medical Center) for MerCreMer mice, T. Yoshimori (Osaka University) for antibody to LC3 and E. Lakatta for teaching us to isolate adult mouse cardiomyocytes. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology to K.O. (16590683). O.Y. held a postdoctoral fellowship from the Japan Society for the Promotion of Science. S.H. was the recipient of a postdoctoral fellowship from the Center of Excellence Research of the Ministry of Education, Culture, Sports, Science and Technology. T.T. received a postdoctoral fellowship from the Japan Health Science Foundation.
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Author notes
- Atsuko Nakai and Osamu Yamaguchi: These authors contributed equally to this work.
Authors and Affiliations
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
Atsuko Nakai, Osamu Yamaguchi, Toshihiro Takeda, Yoshiharu Higuchi, Shungo Hikoso, Masayuki Taniike, Shigemiki Omiya, Isamu Mizote, Kazuhiko Nishida, Masatsugu Hori & Kinya Otsu - Department of Medical Information Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
Yasushi Matsumura - Department of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
Michio Asahi - Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Bunkyoku, Tokyo, 113-8613, Japan
Noboru Mizushima - Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyoku, Tokyo, 113-8519, Japan
Noboru Mizushima - Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honmachi, Kawaguchi, 332-0012, Saitama, Japan
Noboru Mizushima
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Contributions
A.N. worked on the in vitro analysis of the mice; O.Y. conducted the in vivo analysis of the mice and wrote the manuscript; T.T. performed adult cardiomyocyte isolation and Ca2+ transient experiments; Y.H. performed ischemia-reperfusion surgery; S.H. assisted with RT-PCR experiments; M.T., S.O. and I.M. contributed to the in vitro experiments; Y.M. performed statistical analysis of the data; M.A. contributed to Ca2+ transient measurements; K.N. contributed to the in vivo experiments; M.H. supervised this project; N.M. provided advice on designing and conducting experiments; K.O. conceived, designed and directed the study.
Corresponding author
Correspondence toKinya Otsu.
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The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Inhibition of autophagy using adenovirus expressing shRNA against Atg7. (PDF 617 kb)
Supplementary Fig. 2
Characterization of _Atg5_flox/flox; MLC2v-Cre+ mice. (PDF 235 kb)
Supplementary Fig. 3
Pressure overload induces cardiac dysfunction in _Atg5_flox/flox; α-MyHC-Cre+ mice. (PDF 372 kb)
Supplementary Fig. 4
Autophagy in pressure overload-induced cardiac remodeling. (PDF 236 kb)
Supplementary Fig. 5
Biochemical analysis of _Atg5_flox/flox; MLC2v-Cre+ hearts after TAC. (PDF 287 kb)
Supplementary Fig. 6
β-adrenergic stress induces cardiac dysfunction in _Atg5_flox/flox; MLC2v-Cre+ mice. (PDF 627 kb)
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Nakai, A., Yamaguchi, O., Takeda, T. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.Nat Med 13, 619–624 (2007). https://doi.org/10.1038/nm1574
- Received: 10 November 2006
- Accepted: 07 March 2007
- Published: 22 April 2007
- Issue Date: May 2007
- DOI: https://doi.org/10.1038/nm1574
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