Angiotensin II regulates phosphorylation of translation elongation factor-2 in cardiac myocytes.
Increased protein synthesis is the cardinal feature of cardiac hypertrophy. We have studied angiotensin II (ANG II)-dependent regulation of eukaryotic elongation factor-2 (eEF-2), an essential component of protein translation required for polypeptide elongation, in rat neonatal cardiac myocytes. eEF2 is fully active in its dephosphorylated state and is inhibited following phosphorylation by eEF2 kinase. ANG II treatment (10(-10) - 10(-7) M) for 30 min produced an AT(1) receptor-specific and concentration- and time-dependent reduction in the phosphorylation of eEF-2. Protein phosphatase 2A (PP2A) inhibitors okadaic acid and fostriecin, but not the PP2B inhibitor FK506, attenuated ANG II-dependent dephosphorylation of eEF-2. ANG II activated mitogen-activated protein kinase, (MAPK) within 10 min of treatment, and blockade of MAPK activation with PD-98059 (1--20 nM) inhibited eEF-2 dephosphorylation. The effect of ANG II on eEF-2 dephosphorylation was also blocked by LY-29004 (1-20 nM), suggesting a role for phosphoinositide 3-kinase, but the mammalian target rapamycin inhibitor rapamycin (10--100 nM) had no effect. Together these results suggest that the ANG II-dependent increase in protein synthesis includes activation of eEF-2 via dephosphorylation by PP2A by a process that involves both PI3K and MAPK.
Everett
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Division of Pediatric Cardiology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia 22908-1356, USA. ade5r@hscmail.mcc.virginia.edu
Stoops
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Nairn
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Brautigan
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D000804:Angiotensin II / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020652:Peptide Elongation Factor 2 / Q000096:biosynthesis / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D054648:Protein Phosphatase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D020652:Peptide Elongation Factor 2; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D020123:Sirolimus