Differential MAP kinase activation and Na(+)/H(+) exchanger phosphorylation by H(2)O(2) in rat cardiac myocytes.
Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H(2)O(2) (50 microM) decreased contractility of adult rat ventricular myocytes. H(2)O(2) caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in adult rat ventricular myocytes. H(2)O(2) (50 microM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 +/- 1.2- and 9.0 +/- 1.6-fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 +/- 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H(2)O(2)-induced Na(+)/H(+) exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 microM). These results demonstrate that H(2)O(2)-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion.
Wei
S
S
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Rothstein
E C
EC
Fliegel
L
L
Dell'Italia
L J
LJ
Lucchesi
P A
PA
D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D017923:Sodium-Hydrogen Exchangers; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases