RRC ID 5345
Author Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J.
Title Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy.
Journal Circ Res
Abstract 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-beta-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.
Volume 100(6)
Pages 914-22
Published 2007-3-30
DOI 10.1161/01.RES.0000261924.76669.36
PII 01.RES.0000261924.76669.36
PMID 17332429
MeSH AMP-Activated Protein Kinases Animals Apoptosis Regulatory Proteins Autophagy / physiology* Beclin-1 Cell Survival / physiology Cells, Cultured Culture Media / pharmacology Enzyme Inhibitors / pharmacology Glucose / metabolism Heterozygote Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Multienzyme Complexes / antagonists & inhibitors Multienzyme Complexes / biosynthesis Multienzyme Complexes / physiology* Myocardial Ischemia / metabolism* Myocardial Reperfusion* Myocytes, Cardiac / cytology Myocytes, Cardiac / drug effects Myocytes, Cardiac / metabolism* Organ Specificity Protein Kinases / metabolism Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / biosynthesis Protein Serine-Threonine Kinases / physiology* Proteins / genetics Proteins / physiology* Rats Signal Transduction TOR Serine-Threonine Kinases
IF 14.467
Times Cited 981
Mice RBRC00806