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1 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA
2 Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
* To whom correspondence should be addressed. E-mail: murphy1{at}niehs.nih.gov.
Activation of protein kinase C (PKC) is cardioprotective, but the mechanism(s) by which PKC mediates protection is not fully understood. As PKC has been well documented to modulate sarcoplasmic reticulum (SR) Ca2+, and since altered SR Ca2+ handling during ischemia is involved in cardioprotection, we examined the role of PKC mediated alterations of SR Ca2+ in cardioprotection. Using isolated adult rat ventricular myocytes we found that addition of 1,2-dioctanoyl-sn-glycerol (DOG), to activate PKC under conditions that reduced myocyte death following simulated ischemia and reperfusion, also reduced SR Ca2+. Cell death was 57.9 ± 2.9 % in untreated vs. 47.3 ± 1.8 % in DOG treated myocytes (P<0.05). We examined the effect of DOG on SR Ca2+ using fura-2 fluorescence to monitor calcium transients and caffeine-releasable SR Ca2+. Caffeine-releasable SR Ca2+ was significantly reduced (by ~65%) after 10 min of DOG treatment compared to untreated myocytes (P<0.05). We examined the mechanism by which PKC alters SR Ca2+ and present the novel finding that DOG treatment reduced the phosphorylation of phospholamban (PLB) at Ser16. This effect is mediated by PKC-
, since a PKC- selective inhibitory peptide blocked the DOG mediated decrease in phosphorylation of PLB and abolished the DOG induced reduction in caffeine-releasable SR Ca2+. Using immunoprecipitation, we further demonstrated that DOG increased the association between protein phosphatase-1 (PP-1) and PLB. These data suggest that activated PKC- reduces SR Ca2+ content through PLB dephosphorylation, and that reduced SR Ca2+ may be important in cardioprotection.
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