Protein kinase C activation aggravates hypoxic myocardial injury by stimulating Na+/H+ exchange.
The physiological and pathophysiological roles of protein kinase C activation were investigated in cultured mouse myocardial cells. First, effects of 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), a potent activator of protein kinase C, on the intracellular pH (pHi) and cytosolic free Ca2+ level [( Ca2+]i) were studied, using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) and quin-2, respectively. In the presence of the Ca ionophore A23187, TPA induced a rise in pHi by activating amiloride-sensitive Na+/H+ exchange and also produced a rise in [Ca2+]i above that seen with A23187 alone. These effects were totally inhibited by amiloride. Second, the effect of TPA on hypoxia-induced myocardial cell injury was evaluated. The addition of TPA to the culture medium enhanced creatine kinase release from hypoxic myocardial cells (95% N2 + 5% CO2). This effect was markedly suppressed by the addition of amiloride. These data suggests that protein kinase C activation aggravates hypoxic myocardial injury, presumably by inducing Ca2+ overload. This event is secondary to activation of Na+/Ca2+ exchange through accelerated influx of Na+ into the cells as a result of Na+/H+ exchange stimulation by protein kinase C.
Ikeda
U
U
Department of Cardiology, Jichi Medical School, Tochigi, Japan.
Arisaka
H
H
Takayasu
T
T
Takeda
K
K
Natsume
T
T
Hosoda
S
S
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000378:metabolism; D004789:Enzyme Activation; D005333:Fetus / Q000166:cytology; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000473:pathology*; D007474:Ion Exchange; D051379:Mice; D009206:Myocardium / Q000473:pathology; D011493:Protein Kinase C / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D011493:Protein Kinase C; D003402:Creatine Kinase; D013755:Tetradecanoylphorbol Acetate