NO donor-activated PKC-delta plays a pivotal role in ischemic myocardial protection through accelerated opening of mitochondrial K-ATP channels.
Nitric oxide (NO) can activate protein kinase C (PKC) and the activation of mitochondrial ATP-sensitive potassium (K-ATP) channels is cardioprotective. However, interactions among NO, PKC, and mitochondrial K-ATP channels remain vague. To clarify the cardioprotective mechanism induced by nicorandil, we compared its ability to activate PKC isoforms with that of the mitochondrial K-ATP channel opener, diazoxide. We induced myocardial infarction in rats by 30 minutes of ischemia followed by reperfusion, then assessed the infarct size 3 weeks later. We also examined the translocation of PKC isoforms in the isolated perfused rat heart. Nicorandil and diazoxide reduced infarct size, and the effect of nicorandil, but not of diazoxide attenuated by the PKC inhibitor, chelerythrine, or by the NO quencher, carboxy PTIO. Immunoblotting revealed that nicorandil translocated PKC-delta to the mitochondria, and that this was inhibited by carboxy PTIO. The protective effect of nicorandil against myocardial infarction partly depended on the translocation of PKC-delta to the mitochondria, which we attributed to the NO donor effect of nicorandil. The PKC-delta- dependent activation of mitochondrial K-ATP channel opening might be synergistic with its direct effect, making nicorandil an efficient opener of such channels.
Harada
Nozomu
N
Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Miura
Toshiro
T
Dairaku
Yuka
Y
Kametani
Ryosuke
R
Shibuya
Masaki
M
Wang
Ruijuan
R
Kawamura
Shuji
S
Matsuzaki
Masunori
M
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D003981:Diazoxide / Q000627:therapeutic use*; D004789:Enzyme Activation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000517:prevention & control*; D020108:Nicorandil / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000502:physiology*; D015221:Potassium Channels; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D051381:Rats; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; D009569:Nitric Oxide; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D003981:Diazoxide