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Cardioprotection involves activation of NF-B via PKC-dependent tyrosine and serine phosphorylation of IB-

¹Departments of Physiology and Medicine, Cardiovascular Research Laboratories, University of California, Los Angeles, California 90095; and ²Experimental Research Laboratory, Division of Cardiology, University of Louisville, Louisville, Kentucky 40202

Submitted 8 May 2003 ; accepted in final form 5 June 2003

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

ischemic preconditioning; Src tyrosine kinase; protein kinase C; signaling module; posttranslational modification

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