Cardioprotection involves activation of NF-kappa B via PKC-dependent tyrosine and serine phosphorylation of I kappa B-alpha.
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.
Zhang
Jun
J
Department of Physiology, Cardiovascular Research Laboratories, University of California Los Angeles, CA 90095, USA.
Ping
Peipei
P
Vondriska
Thomas M
TM
Tang
Xian-Liang
XL
Wang
Guang-Wu
GW
Cardwell
Ernest M
EM
Bolli
Roberto
R
D000818:Animals; D051550:I-kappa B Kinase; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011817:Rabbits; D012694:Serine / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D007527:Isoenzymes; D016328:NF-kappa B; D014443:Tyrosine; D012694:Serine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D011493:Protein Kinase C