Mechanism of induction of muscle protein degradation by angiotensin II.
Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-kappaB kinase (IKK), which is responsible for the phosphorylation and subsequent degradation of I-kappaB. Both angiotensin I and II induced an early decrease in cytoplasmic I-kappaB levels followed by nuclear accumulation of NF-kappaB. Using an NF-kappaB luciferase construct this was shown to increase transcriptional activation of NF-kappaB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-kappaB, confirming that activation of NF-kappaB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-kappaB.
Russell
Steven T
ST
Biomolecular Sciences, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
Wyke
Stacey M
SM
Tisdale
Michael J
MJ
D021581:Active Transport, Cell Nucleus; D000803:Angiotensin I / Q000502:physiology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D015533:Transcriptional Activation
D001798:Blood Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D009281:Naphthalenes; D011509:Proteoglycans; D013267:Stilbenes; C042057:proteolysis-inducing peptide; D000804:Angiotensin II; D000803:Angiotensin I; D008156:Luciferases; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D046988:Proteasome Endopeptidase Complex; C058819:calphostin C; D000077185:Resveratrol