Cardioprotection involves activation of NF-kappa B via PKC-dependent tyrosine and serine phosphorylation of I kappa B-alpha

Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1753-8. doi: 10.1152/ajpheart.00416.2003. Epub 2003 Jun 26.

Abstract

Previous studies indicated that activation of PKC and Src tyrosine kinases by ischemic preconditioning (PC) may participate in the activation of NF-kappa B. However, the molecular mechanisms underlying activation of NF-kappa B during ischemic PC remain unknown. In the hearts of conscious rabbits, it was found that ischemic PC (6 cycles of 4-min coronary occlusion and 4-min reperfusion) significantly induced both tyrosine (+226.9 +/- 42%) and serine (+137.0 +/- 36%) phosphorylation of the NF-kappa B inhibitory protein I kappa B-alpha, concomitant with increased activation of the I kappa B-alpha kinases IKK alpha (+255.0 +/- 46%) and IKK beta (+173.1 +/- 35%). Furthermore, both tyrosine and serine phosphorylation of I kappa B-alpha were blocked by pretreatment with either the nonreceptor tyrosine kinase inhibitor lavendustin-A (LD-A) or the PKC inhibitor chelerythrine (Che) (both given at doses previously shown to block ischemic PC). Interestingly, Che completely abolished PC-induced activation of IKK alpha/beta, whereas LD-A had no effect. In addition, I kappa B-alpha protein level did not change during ischemic PC. Together, these data indicate that ischemic PC-induced activation of NF-kappa B occurs through both tyrosine and serine phosphorylation of I kappa B-alpha and is regulated by nonreceptor tyrosine kinases and PKC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • I-kappa B Kinase
  • In Vitro Techniques
  • Ischemic Preconditioning, Myocardial*
  • Isoenzymes / metabolism
  • Myocardium / metabolism*
  • NF-kappa B / physiology*
  • Phosphorylation
  • Protein Kinase C / physiology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Protein-Tyrosine Kinases / physiology
  • Rabbits
  • Serine / metabolism*
  • Tyrosine / metabolism*

Substances

  • Isoenzymes
  • NF-kappa B
  • Tyrosine
  • Serine
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • Protein Kinase C