Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I).
Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase Calpha (PKCalpha), degradation of inhibitor-kappaB (I-kappaB) and nuclear migration of nuclear factor-kappaB (NF-kappaB), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the alpha-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase 1, which dephosphorylates PKR. Release of arachidonic acid and activation of PKCalpha by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 muM), an inhibitor of eIF2alpha dephosphorylation, as was activation of PKCalpha. In addition myotubes transfected with a dominant-negative PKR (PKRDelta6) showed no release of arachidonate in response to Ang II, and no activation of PKCalpha. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA(2)/PKC pathway leading to activation of NF-kappaB and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR.
Russell
Steven T
ST
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Eley
Helen
H
Tisdale
Michael J
MJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014316:Tritium; D025801:Ubiquitin / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D002934:Cinnamates; D020717:Eukaryotic Initiation Factor-2B; D025801:Ubiquitin; C496827:salubrinal; D014316:Tritium; D000804:Angiotensin II; D016718:Arachidonic Acid; D007334:Insulin-Like Growth Factor I; D019892:eIF-2 Kinase; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; D013890:Thiourea