Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection

Nishino, Yasuhiro; Miura, Tetsuji; Miki, Takayuki; Sakamoto, Jun; Nakamura, Yūichi; Ikeda, Yoshihiro; Kobayashi, Hironori; Shimamoto, Kazuaki

doi:10.1016/j.cardiores.2003.10.022

Cited by 139 publications

(107 citation statements)

References 41 publications

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“…Ucn2 is known to stimulate PKCe translocation (34), but only limited prior data exist linking PKCe with AMPK (35). Pharmacologic PKC inhibitors abolished AMPK activation in the ischemic heart, but an unexpected high degree of AMPK inhibition was observed that likely reflected the known lack of specificity of these inhibitors (36).…”

Section: Discussionmentioning

confidence: 97%

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Qi²,

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) on cardiomyocytes and confers protection against ischemia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis mitigates against ischemia/reperfusion injury remain incompletely delineated. Activation of AMP-activated protein kinase (AMPK) also limits cardiac damage during ischemia/reperfusion. AMPK is classically activated by alterations in cellular energetics; however, hormones, cytokines, and additional autocrine/paracrine factors also modulate its activity. We examined the effects of both the endogenous cardiac Ucn2 autocrine/paracrine pathway and Ucn2 treatment on AMPK regulation. Ucn2 treatment increased AMPK activation and downstream acetyl-CoA carboxylase phosphorylation and glucose uptake in isolated heart muscles. These actions were blocked by the CRFR2 antagonist anti-sauvagine-30 and by a PKCe translocation-inhibitor peptide (eV1-2). Hypoxia-induced AMPK activation was also blunted in heart muscles by preincubation with either anti-sauvagine-30, a neutralizing anti-Ucn2 antibody, or eV1-2. Treatment with Ucn2 in vivo augmented ischemic AMPK activation and reduced myocardial injury and cardiac contractile dysfunction after regional ischemia/reperfusion in mice. Ucn2 also directly activated AMPK in ex vivo-perfused mouse hearts and diminished injury and contractile dysfunction during ischemia/reperfusion. Thus, both Ucn2 treatment and the endogenous cardiac Ucn2 autocrine/paracrine pathway activate AMPK signaling pathway, via a PKCe-dependent mechanism, defining a Ucn2-CRFR2-PKCe-AMPK pathway that mitigates against ischemia/reperfusion injury. metabolism | cardiac function

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Section: Discussionmentioning

confidence: 97%

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Qi²,

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…We first demonstrated that AMPK activation occurs during myocardial ischemia, 2,3 a finding now reproduced by numerous laboratories. 4,[7][8][9][10][11]23,24 This activation of AMPK presumably occurs as an approach to restore myocyte ATP levels, primarily turning on ATP generating pathways. It is now clear that AMPK activation can increase both glucose and fatty acid metabolism in the ischemic heart.…”

Section: Ampk Activation During Ischemia/reperfusionmentioning

confidence: 99%

“…Similar to what had been previously observed in liver, 40 ischemic preconditioning activates AMPK in the heart. 23,41 This activation of AMPK is associated with an upregulation of GLUT4 expression, which occurs in a protein kinase C-dependent manner. 23 The activation of H11 kinase that occurs in preconditioned hearts is also associated with an activation of AMPK and promotes the translocation of AMPK to the nucleus (presumably resulting in an increase in transcription of proteins such as GLUT4).…”

Section: Is Ampk Activation Beneficial or Harmful During And Followinmentioning

confidence: 99%

“…23,41 This activation of AMPK is associated with an upregulation of GLUT4 expression, which occurs in a protein kinase C-dependent manner. 23 The activation of H11 kinase that occurs in preconditioned hearts is also associated with an activation of AMPK and promotes the translocation of AMPK to the nucleus (presumably resulting in an increase in transcription of proteins such as GLUT4). This activation of AMPK and increase in glucose uptake in ischemic preconditioning has the potential to benefit the heart.…”

Section: Is Ampk Activation Beneficial or Harmful During And Followinmentioning

confidence: 99%

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AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk

2008

Int J Obes

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Myocardial ischemia produces an energy-deficient state in heart muscle, which if not corrected can lead to cardiomyocyte death. AMP-activated protein kinase (AMPK) is a key kinase that can increase energy production in the ischemic heart. During ischemia a rapid activation of AMPK occurs, resulting in an activation of both myocardial glucose uptake and glycolysis, as well as an increase in fatty acid oxidation. This activation of AMPK has the potential to increase energy production, thereby protecting the heart during ischemic stress. However, at clinically relevant high levels of fatty acids, ischemia-induced activation of AMPK also stimulates fatty acid oxidation during and following ischemia. This can contribute to ischemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency. As a result, AMPK activation has the potential to be either beneficial or harmful in the ischemic heart.

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“…Glucose homeostasis is maintained by a balance between hepatic glucose production and glucose uptake by peripheral tissues. Activation of AMP-activated protein kinase (AMPK) 2 enhances glucose uptake through the translocation of the glucose transporter 4 (GLUT4) to the cell membrane and also through regulation of Glut4 gene expression (1)(2)(3). The AMPK activator enhances glucose uptake into muscle by increasing cell surface GLUT4 levels (4 -6).…”

mentioning

confidence: 99%

E3 Ubiquitin Ligase, WWP1, Interacts with AMPKα2 and Down-regulates Its Expression in Skeletal Muscle C2C12 Cells

Lee

Kim

et al. 2013

Journal of Biological Chemistry

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Background:The role of the ubiquitin-proteasome pathway under high glucose conditions is unclear. Results: AMPK␣2 interacts with WWP1, and its expression is down-regulated by the ubiquitin proteasome pathway in high glucose culture conditions in C2C12 cells. Conclusion: WWP1 down-regulates AMPK␣2 expression through direct interaction in high glucose culture conditions of skeletal muscle C2C12 cells. Significance: The ubiquitin proteasome pathway may involve high glucose-induced AMPK␣2 down-regulation.

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Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection

Abstract: PC activated AMPK and up-regulated GLUT4 expression in a PKC-dependent manner. This GLUT4 up-regulation at 24 h after PC may contribute to attenuation of myocardial stunning.

Cited by 139 publications

References 41 publications

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

AMP-activated protein kinase control of energy metabolism in the ischemic heart

E3 Ubiquitin Ligase, WWP1, Interacts with AMPKα2 and Down-regulates Its Expression in Skeletal Muscle C2C12 Cells

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