title: Cardioplegia and angiotensin II receptor antagonists modulate signal transducers and activators of transcription activation in neonatal rat myocytes.
abstract: Previous investigations have shown that the signal transducers and activators of transcription (STATs) signaling pathway play an important role in the modulation of apoptosis after ischemia and reperfusion. The mechanism for this enhanced cardioprotection is unknown, but we believe that alterations STATs may play a role. To investigate this hypothesis, we examined the effects of angiotension II type 1 (AT1) and angiotension II type 2 (AT2) receptor antagonist added to cardioplegia on the downstream response of different STATs, connected with proinflammatory pathways (STAT2, STAT5) and prohypertrophic and antiapoptotic pathways (STAT3). Isolated, nonworking hearts (n = 3 per group) from neonatal rats were perfused aerobically (4°C) for 20 min in the Langendorff mode with the modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 1), the MSTH2 cardioplegic solution + AT1 receptor antagonist (Group 2), and MSTH2 cardioplegic solution + AT2 receptor antagonist (Group 3). Thus, myocytes were isolated by enzymatic digestion, and STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 8-12 s for all groups. Total cardioplegia delivery volume was about 300 mL for the 20 min. Perfusion with the MSTH2 cardioplegic solution supplemented with AT1 receptor antagonist (Group 2) induced a significant reduction in STAT2 and STAT5 tyrosine phosphorylation (-58 and -63%, respectively, vs. Group 1, P < 0.05). Conversely, STAT2 and STAT5 activation were unaffected by perfusion with the MSTH2 cardioplegic solution supplemented with AT2 receptor antagonist (Group 3). The decreased activation of STAT2 and STAT5 observed in Group 2 was accompanied by reduction of interleukin-1β (-57% in Group 2 vs. Group 1, P < 0.05). There were no significant differences in STAT3 phosphorylation among all groups. Only the addition of AT1 receptor antagonist to MSTH2 cardioplegia significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by tyrosine phosphorylation of STAT3. AT1 receptor antagonist added to cardioplegia represents an additional modality for enhancing myocardial protection during cardiac surgery and could contribute to optimize the ischemia tolerance of the pediatric heart.
authors.affiliation: Division of Cardiac Surgery, University of Verona, Verona, Italy. gianluca.lucchese@univr.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Lucchese
authors.forename: Giulia Elisa
authors.initials: GE
authors.lastname: Cambi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Rita
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faggian
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mazzucco
authors.forename: Pietro Amedeo
authors.initials: PA
authors.lastname: Modesti
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Luciani
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006324:Heart Arrest, Induced; D007093:Imidazoles / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D050791:STAT Transcription Factors; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D013777:Tetrazoles; C073402:PD 123319; D000068756:Valsartan; D014633:Valine