AMPK Mediates Autophagy during Myocardial Ischemia In Vivo

Takagi, Hiromitsu; Matsui, Yutaka; Hirotani, Shinichi; Sakoda, Hideyuki; Asano, Tomohiko; Sadoshima, Junichi

doi:10.4161/auto.4281

Cited by 146 publications

(125 citation statements)

References 14 publications

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“…As a sensor of energy stress, AMPK may regulate autophagy through different downstream signals including inhibition of mTOR, phosphorylation of eukaryotic elongation factor-2 kinase, phosphorylation of p27, and direct activation of autophagic genes. 45 In addition to AMPK, HIF-1-induced REDD also contributes to mTOR inhibition, thus integrating the two O 2 -sensing pathways (HIF-1 and mTOR) for autophagy induction. 46 Recently, endoplasmic reticulum stress through unfolded protein response and intracellular calcium has been implicated in autophagy regulation.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury

Jiang

Liu

Luo

et al. 2010

The American Journal of Pathology

341

349

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Autophagy mediates bulk degradation and recycling of cytoplasmic constituents to maintain cellular homeostasis. In response to stress , autophagy is induced and may either contribute to cell death or serve as a cell survival mechanism. Very little is known about autophagy in renal pathophysiology. This study examined autophagy and its pathological role in renal cell injury using in vitro and in vivo models of ischemia؊reperfusion. We found that hypoxia (1% O 2 ) induced autophagy in cultured renal proximal tubular cells. Blockade of autophagy by 3-methyladenine or small-interfering RNA knockdown of Beclin-1 and ATG5 (two key autophagic genes) sensitized the tubular cells to hypoxia-induced apoptosis.In an in vitro model of ischemia؊reperfusion , autophagy was not induced by anoxic (0% O 2 ) incubation in glucose-free buffer , but was induced during subsequent recovery/reperfusion period. In this model, suppression of autophagy also enhanced apoptosis. In vivo, autophagy was induced in kidney tissues during renal ischemia؊reperfusion in mice. Autophagy was not obvious during the ischemia period, but was significantly enhanced during reperfusion. Inhibition of autophagy by chloroquine and 3-methyladenine worsened renal ischemia/reperfusion injury , as indicated by renal function , histology , and tubular apoptosis. Together , the results demonstrated autophagy induction during hypoxic and ischemic renal injury. Under these pathological conditions , autophagy may provide a protective mechanism for cell survival. Autophagy is a cellular process of "self-eating" wherein various cytoplasmic constituents are broken down and recycled through the lysosomal degradation pathway. 1This process consists of several sequential steps, including sequestration of cytoplasmic portions by isolation membrane to form autophagosome, fusion of the autophagosome with lysosome to create an autolysosome, and degradation of the engulfed material to generate monomeric units such as amino acids.2 Identification of the autophagy-related genes (ATG) in yeast and their orthologs in other organisms including mammals demonstrates that autophagy is evolutionarily conserved in all eukaryotic cells. The ATG genes constitute the core molecular machinery of autophagy and function at the different levels to regulate autophagy induction, progression, and completion. 1 Autophagy occurs at basal level in most cells and contributes to the turnover of long-lived proteins and organelles to maintain intracellular homeostasis. In response to cellular stress, autophagy is up-regulated and can provide an adaptive strategy for cell survival, but may also directly or indirectly lead to cell demise. [3][4][5][6] With the dual role in life and death, autophagy is involved in various physiological processes, and more importantly, linked to the pathogenesis of a wide array of diseases, such as neurodegeneration, cancer, heart disease, aging, and infections.1,2,6,7 However, it remains largely unknown how autophagy makes the life and death decisions of a stressed cell. ...

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Section: Discussionmentioning

confidence: 99%

Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury

Jiang

Liu

Luo

et al. 2010

The American Journal of Pathology

341

349

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“…10,[12][13][14][15] Our laboratory first demonstrated that chronic myocardial ischemia induces autophagy in vivo, i.e., autophagy contributes to cardioprotection against apoptosis in chronically ischemic myocardium in swine. 16 Interestingly, distinct roles of autophagy during acute ischemia and reperfusion in the mouse heart are reported, showing a protective role during ischemia, but a detrimental effect during reperfusion.…”

Section: Autophagy In the Heart: Ischemia/reperfusionmentioning

confidence: 99%

Autophagy in ischemic preconditioning and hibernating myocardium

Lin¹,

Sadoshima

Vatner

et al. 2009

Autophagy

Self Cite

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“…It has also been reported that the absence of AMPK aggravated myocardial infarct size in mouse hearts subjected to ischemia, which is associated with autophagosomal formation. These results suggest that the up-regulatiion of autophagy mediated by the AMPK-mTOR pathway has a beneficial effect on cell survival during ischemia [24] . AMPK has been shown to contribute to the protective effects of ischemic preconditioning in neurons.…”

Section: Ampk and Mtormentioning

confidence: 71%

“…When the autophagy mediated by Beclin1 was inhibited through the siRNA-mediated downregulation of Beclin1 expression in cultured cardiomyocytes, the cellular survival increased after ischemic damage [31] . Mice containing a heterozygous disruption of Beclin1 exhibited an inhibition of autophagy, a decrease in apoptosis and a reduction in infarct size during myocardial ischemia-reperfusion [24] . However, it is unknown whether the autophagy induced by Beclin1 is detrimental or protective.…”

Section: Beclinmentioning

confidence: 99%

“…During ischemic injury in the heart, the cellular ATP content decreases and AMP accumulates because of energy depletion, which activates the AMP-activated protein kinase (AMPK). The activation of AMPK suppresses mTOR activity, thereby up-regulating autophagy [24] , indicating that the pathway for AMPK-mTOR is important for autophagy regulation. It has been reported that in cultured cardiomyocytes exposed to glucose deprivation, the level of ATP was reduced significantly, leading to the activation of AMPK and suppression of mTOR, which was coincident with the up-regulation of autophagy.…”

Section: Ampk and Mtormentioning

confidence: 99%

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The protective roles of autophagy in ischemic preconditioning

2013

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Autophagy, a process for the degradation of protein aggregates and dysfunctional organelles, is required for cellular homeostasis and cell survival in response to stress and is implicated in endogenous protection. Ischemic preconditioning is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion through the up-regulation of endogenous protective mechanisms. Emerging evidence shows that autophagy is associated with the protective effect of ischemic preconditioning. This review summarizes recent progress in research on the functions and regulations of the autophagy pathway in preconditioning-induced protection and cellular survival.

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AMPK Mediates Autophagy during Myocardial Ischemia In Vivo

Cited by 146 publications

References 14 publications

Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury

Autophagy Is a Renoprotective Mechanism During in Vitro Hypoxia and in Vivo Ischemia-Reperfusion Injury

Autophagy in ischemic preconditioning and hibernating myocardium

The protective roles of autophagy in ischemic preconditioning

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