Published online before print March 1, 2007, doi: 10.1161/01.RES.0000261924.76669.36
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 1, 2006
Revised on January 31, 2007
Accepted on January 20, 2007
Distinct Roles of Autophagy in the Heart During Ischemia and Reperfusion. Roles of AMP-Activated Protein Kinase and Beclin 1 in Mediating Autophagy
Yutaka Matsui ;
From the Cardiovascular Research Institute (Y.M., H.T., M.A., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; Departments of Internal Medicine and Microbiology (X.Q., B.L.), University of Texas Southwestern Medical Center, Dallas; Department of Internal Medicine (H.S.), Graduate School of Medicine, University of Tokyo, Japan; and Division of Molecular Medical Science (T.A.), Programs for Biomedical Research, Hiroshima University, Japan.
* To whom correspondence should be addressed. E-mail: Sadoshju{at}umdnj.edu.
Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-
-D-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1+/- mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.
Key words: autophagy • AMP-activated protein kinase (AMPK) • beclin 1 • ischemia/reperfusion
This article has been cited by other articles:
 |
|
 |
|
  Y. Inuzuka, J. Okuda, T. Kawashima, T. Kato, S. Niizuma, Y. Tamaki, Y. Iwanaga, Y. Yoshida, R. Kosugi, K. Watanabe-Maeda, et al. Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice Circulation, October 27, 2009; 120(17): 1695 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sengupta, J. D. Molkentin, and K. E. Yutzey FoxO Transcription Factors Promote Autophagy in Cardiomyocytes J. Biol. Chem., October 9, 2009; 284(41): 28319 - 28331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Su and X. Wang The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective Cardiovasc Res, September 16, 2009; (2009) cvp287v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Luo, J. Wong, and B. Wong Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy Cardiovasc Res, August 6, 2009; (2009) cvp225v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, X. Kong, J. Kang, J. Su, Y. Li, J. Zhong, and L. Sun Oxidative Stress Induces Parallel Autophagy and Mitochondria Dysfunction in Human Glioma U251 Cells Toxicol. Sci., August 1, 2009; 110(2): 376 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Periyasamy-Thandavan, M. Jiang, P. Schoenlein, and Z. Dong Autophagy: molecular machinery, regulation, and implications for renal pathophysiology Am J Physiol Renal Physiol, August 1, 2009; 297(2): F244 - F256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. R. Porrello, A. D'Amore, C. L. Curl, A. M. Allen, S. B. Harrap, W. G. Thomas, and L. M.D. Delbridge Angiotensin II Type 2 Receptor Antagonizes Angiotensin II Type 1 Receptor-Mediated Cardiomyocyte Autophagy Hypertension, June 1, 2009; 53(6): 1032 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kanamori, G. Takemura, R. Maruyama, K. Goto, A. Tsujimoto, A. Ogino, L. Li, I. Kawamura, T. Takeyama, T. Kawaguchi, et al. Functional Significance and Morphological Characterization of Starvation-Induced Autophagy in the Adult Heart Am. J. Pathol., May 1, 2009; 174(5): 1705 - 1714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Weisova, C. G. Concannon, M. Devocelle, J. H. M. Prehn, and M. W. Ward Regulation of Glucose Transporter 3 Surface Expression by the AMP-Activated Protein Kinase Mediates Tolerance to Glutamate Excitation in Neurons J. Neurosci., March 4, 2009; 29(9): 2997 - 3008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Gustafsson and R. A. Gottlieb Autophagy in Ischemic Heart Disease Circ. Res., January 30, 2009; 104(2): 150 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhu, M. H. Soonpaa, H. Chen, W. Shen, R. M. Payne, E. A. Liechty, R. L. Caldwell, W. Shou, and L. J. Field Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway Circulation, January 6, 2009; 119(1): 99 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roos, O. Lagerlof, M. Wennergren, T. L. Powell, and T. Jansson Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling Am J Physiol Cell Physiol, January 1, 2009; 297(3): C723 - C731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Rothermel and J. A. Hill Autophagy in Load-Induced Heart Disease Circ. Res., December 5, 2008; 103(12): 1363 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Itakura, C. Kishi, K. Inoue, and N. Mizushima Beclin 1 Forms Two Distinct Phosphatidylinositol 3-Kinase Complexes with Mammalian Atg14 and UVRAG Mol. Biol. Cell, December 1, 2008; 19(12): 5360 - 5372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hara, A. Takamura, C. Kishi, S.-i. Iemura, T. Natsume, J.-L. Guan, and N. Mizushima FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells J. Cell Biol., October 14, 2008; 181(3): 497 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-L. Yen and D. J. Klionsky How to Live Long and Prosper: Autophagy, Mitochondria, and Aging Physiology, October 1, 2008; 23(5): 248 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Maruyama, K. Goto, G. Takemura, K. Ono, K. Nagao, T. Horie, A. Tsujimoto, H. Kanamori, S. Miyata, H. Ushikoshi, et al. Morphological and biochemical characterization of basal and starvation-induced autophagy in isolated adult rat cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1599 - H1607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nishida, O. Yamaguchi, and K. Otsu Crosstalk Between Autophagy and Apoptosis in Heart Disease Circ. Res., August 15, 2008; 103(4): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Melendez and T. P. Neufeld The cell biology of autophagy in metazoans: a developing story Development, July 15, 2008; 135(14): 2347 - 2360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Tannous, H. Zhu, J. L. Johnstone, J. M. Shelton, N. S. Rajasekaran, I. J. Benjamin, L. Nguyen, R. D. Gerard, B. Levine, B. A. Rothermel, et al. Autophagy is an adaptive response in desmin-related cardiomyopathy PNAS, July 15, 2008; 105(28): 9745 - 9750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hill and E. N. Olson Cardiac Plasticity N. Engl. J. Med., March 27, 2008; 358(13): 1370 - 1380. [Full Text] [PDF]
|
|
|
|
|
|
L. H. Young AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Circulation, February 12, 2008; 117(6): 832 - 840. [Full Text] [PDF]
|
|
|
|
|
|
A. B. Gustafsson and R. A. Gottlieb Heart mitochondria: gates of life and death Cardiovasc Res, January 15, 2008; 77(2): 334 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mizushima Autophagy: process and function Genes & Dev., November 15, 2007; 21(22): 2861 - 2873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Gills, J. LoPiccolo, J. Tsurutani, R. H. Shoemaker, C. J.M. Best, M. S. Abu-Asab, J. Borojerdi, N. A. Warfel, E. R. Gardner, M. Danish, et al. Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo Clin. Cancer Res., September 1, 2007; 13(17): 5183 - 5194. [Abstract] [Full Text] [PDF]
|
|