Mechanism of induction of muscle protein degradation by angiotensin II

Cell Signal. 2006 Jul;18(7):1087-96. doi: 10.1016/j.cellsig.2005.09.009. Epub 2005 Oct 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Angiotensin I / physiology
  • Angiotensin II / physiology*
  • Animals
  • Blood Proteins / metabolism
  • Cell Line
  • Enzyme Activation
  • I-kappa B Kinase / metabolism
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Mice
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Naphthalenes / pharmacology
  • Proteasome Endopeptidase Complex / biosynthesis*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Proteoglycans
  • Resveratrol
  • Signal Transduction
  • Stilbenes / pharmacology
  • Transcriptional Activation

Substances

  • Blood Proteins
  • Muscle Proteins
  • NF-kappa B
  • Naphthalenes
  • Proteoglycans
  • Stilbenes
  • proteolysis-inducing peptide
  • Angiotensin II
  • Angiotensin I
  • Luciferases
  • I-kappa B Kinase
  • Protein Kinase C
  • Proteasome Endopeptidase Complex
  • calphostin C
  • Resveratrol