Background:Cardioplegic arrest even if controlled is a model of ischaemia/reperfusion (I/R) injury and results in the death of irreplaceable cardiac myocytes by a programme cell death or apoptosis. STAT signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. AT1 receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts.Methods:Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode accordingly following scheme: DMEM solution (Group 1); cold (4°C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4°C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); warm (34°C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies.Results:Times to arrest after cardioplegia were 6-10 seconds for all groups with exception of Group 1 (spontaneously arrest after16 seconds). Total cardioplegia delivery volume was about 300 mL in 15 minutes. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2 and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2 and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1β (P < 0.05). Differently, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05).Conclusions:Only perfusion with AT1 receptor antagonist supplemented cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants.
Angiotensin II Type 1 (AT1) Receptor Antagonist Not Cardioplegia Temperature Regulates Activation of Pro-Inflammatory Signal Transducers and Activators of Transcription (STAT) Proteins in Neonatal Rat Myocytes.
LUCCHESE, Gianluca;DE RITA, Fabrizio;FAGGIAN, Giuseppe;MAZZUCCO, Alessandro;LUCIANI, GIOVANNI BATTISTA
2012-01-01
Abstract
Background:Cardioplegic arrest even if controlled is a model of ischaemia/reperfusion (I/R) injury and results in the death of irreplaceable cardiac myocytes by a programme cell death or apoptosis. STAT signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. AT1 receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts.Methods:Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode accordingly following scheme: DMEM solution (Group 1); cold (4°C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4°C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); warm (34°C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies.Results:Times to arrest after cardioplegia were 6-10 seconds for all groups with exception of Group 1 (spontaneously arrest after16 seconds). Total cardioplegia delivery volume was about 300 mL in 15 minutes. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2 and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2 and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1β (P < 0.05). Differently, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05).Conclusions:Only perfusion with AT1 receptor antagonist supplemented cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants.
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