Cardioprotection involves activation of NF-κB via PKC-dependent tyrosine and serine phosphorylation of IκB-α

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Abstract
Previous studies indicated that activation of PKC and Src tyrosine kinases by ischemic preconditioning (PC) may participate in the activation of NF-κB. However, the molecular mechanisms underlying activation of NF-κB 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-κB inhibitory protein IκB-α, concomitant with increased activation of the IκB-α kinases IKKα (+255.0 ± 46%) and IKKβ (+173.1 ± 35%). Furthermore, both tyrosine and serine phosphorylation of IκB-α 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 IKKα/β, whereas LD-A had no effect. In addition, IκB-α protein level did not change during ischemic PC. Together, these data indicate that ischemic PC-induced activation of NF-κB occurs through both tyrosine and serine phosphorylation of IκB-α and is regulated by nonreceptor tyrosine kinases and PKC.