Myocardial Protein Synthesis in Acute Myocardial Hypoxia and Ischemia

Wollenberger, A; Onnen, K; Hinterberger, U; Rabitzsch, G; Kleitke, B

doi:10.1159/000169341

Cited by 7 publications

(3 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibition of protein synthesis by oxygen deprivation is a well-known observation [11][12][13][14][15][16]. Surprisingly, the molecular mechanisms behind this phenomenon have received little attention, although changes in the association of 4E-BP1 and eIF4E have been reported [17,18].…”

Section: Figure S2 In the Supplementary Material) In Cho-k1mentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis

et al. 2002

View full text Add to dashboard Cite

Protein synthesis, in particular peptide-chain elongation, consumes cellular energy. Anoxia activates AMP-activated protein kinase (AMPK, see ), resulting in the inhibition of biosynthetic pathways to conserve ATP. In anoxic rat hepatocytes or in hepatocytes treated with 5-aminoimidazole-4-carboxamide (AICA) riboside, AMPK was activated and protein synthesis was inhibited. The inhibition of protein synthesis could not be explained by changes in the phosphorylation states of initiation factor 4E binding protein-1 (4E-BP1) or eukaryotic initiation factor 2alpha (eIF2alpha). However, the phosphorylation state of eukaryotic elongation factor 2 (eEF2) was increased in anoxic and AICA riboside-treated hepatocytes and in AICA riboside-treated CHO-K1 cells, and eEF2 phosphorylation is known to inhibit its activity. Incubation of CHO-K1 cells with increasing concentrations of 2-deoxyglucose suggested that the mammalian target of the rapamycin (mTOR) signaling pathway did not play a major role in controlling the level of eEF2 phosphorylation in response to mild ATP depletion. In HEK293 cells, transfection of a dominant-negative AMPK construct abolished the oligomycin-induced inhibition of protein synthesis and eEF2 phosphorylation. Lastly, eEF2 kinase, the kinase that phosphorylates eEF2, was activated in anoxic or AICA riboside-treated hepatocytes. Therefore, the activation of eEF2 kinase by AMPK, resulting in the phosphorylation and inactivation of eEF2, provides a novel mechanism for the inhibition of protein synthesis.

show abstract

Section: Figure S2 In the Supplementary Material) In Cho-k1mentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Like insulin, increasing the workload stimulates glycolysis via a wortmannin-sensitive pathway (9, 10). Activation of PI 3-kinase and mTOR could therefore be implicated in the stimulation of protein synthesis by increasing the workload, which was one of the aspects studied in this report.In contrast to insulin and increased workload, oxygen deprivation inhibits protein synthesis (11,12). In skeletal muscle, an inhibition of mTOR/p70S6K signaling following AMP-activated protein kinase (AMPK) activation has been proposed to explain the inhibition of protein synthesis by oxygen deprivation (13).…”

mentioning

confidence: 99%

“…In contrast to insulin and increased workload, oxygen deprivation inhibits protein synthesis (11,12). In skeletal muscle, an inhibition of mTOR/p70S6K signaling following AMP-activated protein kinase (AMPK) activation has been proposed to explain the inhibition of protein synthesis by oxygen deprivation (13).…”

mentioning

confidence: 99%

Myocardial Ischemia and Increased Heart Work Modulate the Phosphorylation State of Eukaryotic Elongation Factor-2

Horman

Beauloye²,

Vertommen

et al. 2003

Journal of Biological Chemistry

119

View full text Add to dashboard Cite

Protein synthesis, in particular peptide chain elongation, is an energy-consuming biosynthetic process. AMPactivated protein kinase (AMPK) is a key regulatory enzyme involved in cellular energy homeostasis. Therefore, we tested the hypothesis that, as in liver, it could mediate the inhibition of protein synthesis by oxygen deprivation in heart by modulating the phosphorylation of eukaryotic elongation factor-2 (eEF2), which becomes inactive in its phosphorylated form. In anoxic cardiomyocytes, AMPK activation was associated with an inhibition of protein synthesis and an increase in phosphorylation of eEF2. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), did not mimic the effect of oxygen deprivation to inhibit protein synthesis in cardiomyocytes or lead to eEF2 phosphorylation in perfused hearts, suggesting that AMPK activation did not inhibit mTOR/p70 ribosomal protein S6 kinase (p70S6K) signaling. Human recombinant eEF2 kinase (eEF2K) was phosphorylated by AMPK in a timeand AMP-dependent fashion, and phosphorylation led to eEF2K activation, similar to that observed in extracts from ischemic hearts. In contrast, increasing the workload resulted in a dephosphorylation of eEF2, which was rapamycin-insensitive, thus excluding a role for mTOR in this effect. eEF2K activity was unchanged by increasing the workload, suggesting that the decrease in eEF2 phosphorylation could result from the activation of an eEF2 phosphatase.Protein synthesis, in particular peptide chain elongation, is an energy-consuming biosynthetic process, accounting for a large proportion of the oxygen requirements of cells (1). Protein synthesis is regulated via the phosphorylation/dephosphorylation of translation factors and ribosomal proteins (2). The mammalian target of rapamycin (mTOR) 1 phosphorylates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), thereby relieving its inhibitory action on eukaryotic initiation factor 4E (eIF-4E), which can then bind the mRNA cap and stimulate protein synthesis (3). The control of translation by mTOR is also exerted at elongation by regulating the phosphorylation of eukaryotic elongation factor-2 (eEF2) (4). The phosphorylation of eEF2 at Thr-56 by a specific calcium-and calmodulin-dependent eukaryotic eEF2 kinase (eEF2K) leads to its inactivation (5). The p70 ribosomal protein S6 kinase (p70S6K) lies downstream of mTOR and phosphorylates Ser-366 of eEF2K, causing inactivation (4). Therefore, mTOR activation can result in a stimulation of protein synthesis by decreasing eEF2 phosphorylation. Indeed, one of the mechanisms by which insulin stimulates protein synthesis in the heart involves mTOR activation, the effect being blocked by the mTOR inhibitor, rapamycin, and by wortmannin, which blocks phosphatidylinositol 3-kinase (PI 3-kinase) upstream of mTOR (6). The stimulation of protein synthesis by insulin also involves a mTOR-independent mechanism via the phosphorylation and inactivation of glycogen synthase kinase-3. Glycogen synthase kinase-3 phosphorylates and inactivates...

show abstract

Genetic Induction of a Cardiomyopathy

Lossnitzer¹

1975

Experimental Production of Diseases: Heart and Circulation

View full text Add to dashboard Cite

Myocardial Protein Synthesis in Acute Myocardial Hypoxia and Ischemia

Cited by 7 publications

References 17 publications

Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis

Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis

Myocardial Ischemia and Increased Heart Work Modulate the Phosphorylation State of Eukaryotic Elongation Factor-2

Genetic Induction of a Cardiomyopathy

Contact Info

Product

Resources

About