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1 Cardiovascular Center, Kansai Medical University, Moriguchi, Japan
* To whom correspondence should be addressed. E-mail: otanih{at}takii.kmu.ac.jp.
Activation of p38MAP kinase (p38MAPK) has been implicated in the mechanism of cardiomyocytes (CMCs) protection and injury. The p38MAPK controversy may be related to differential effects of this kinase on apoptosis and necrosis. We have hypothesized that p38MAPK-mediated F-actin reorganization promotes apoptotic cell death, while it protects from osmotic stress-induced necrotic cell death. Cultured neonatal rat CMCs were subjected to 2 hours of simulated ischemia followed by reoxygenation. p38MAPK activity measured by phosphorylation of MAPKAPK-2 was increased during simulated ischemia and reoxygenation. This was associated with translocation of HSP27 from the cytosolic to the cytoskeletal fraction and F-actin reorganization. Cytochrome c release from mitochondria, caspase 3 activation, and DNA fragmentation were increased during reoxygenation. Robust LDH release was observed under hyposmotic (140 mosm) reoxygenation. The p38MAPK inhibitor SB203580 abrogated activation of p38MAPK, translocation of HSP27, and F-actin reorganization and prevented cytochrome c release, caspase 3 activation, and DNA fragmentation. Conversely, SB203580 enhanced LDH release during hyposmotic reoxygenation. The F-actin disrupting agent cytochalasin D inhibited F-actin reorganization and prevented cytochrome c release, caspase 3 activation, and DNA fragmentation, while it enhanced LDH release during hyposmotic reoxygenation. When CMCs were incubated under the isosmotic condition for the first 15 minutes of reoxygenation, SB203580 and cytochalasin D increased ATP content of CMCs and prevented LDH release after the conversion to the hyposmotic condition. These results suggest that F-actin reorganization mediated by activation of p38MAPK plays a differential role in apoptosis and protection against osmotic stress-induced necrosis during reoxygenation in neonatal rat CMCs, however, that the sarcolemmal fragility caused by p38MAPK inhibition can be reversed during temporary blockade of physical stress during reoxygenation.
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