OBJECTIVE: Apoptotic processes may be implicated in the molecular pathomechanisms of ventricular remodeling after myocardial infarction (MI). The modulation of apoptosis by pro- and anti-apoptotic pathways in the myocardium remote from the infarction, including its link to protein kinase C (PKC), was focus of the present study. METHODS: Rats were subjected to MI by LAD ligation in situ. Some animals were pretreated with the PKC inhibitor chelerythrine. After 1 h up to 28 days, pro- and anti-apoptotic signals (caspase-3, Bcl-2/Bax ratio, Akt, Bad), and marker of apoptosis execution (DNA laddering, TUNEL) were quantified in the myocardium remote from the infarction. RESULTS: Activation of caspase-3, a pro-apoptotic shift of the Bcl-2/Bax ratio, and DNA fragmentation were observed as early as 3 h after infarction and persisted up to 28 days. Akt- and Bad-phosphorylation was unchanged. Chelerythrine markedly reduced DNA fragmentation. Caspase-3 activation was unchanged. Surprisingly, Bad and Akt phosphorylation were highly increased (180% and 750% of control). CONCLUSION: Chelerythrine influences the balance of pro- and anti-apoptotic pathways in the remote myocardium after infarction, with an inhibition of proapoptotic and an activation of anti-apoptotic signals.
OBJECTIVE: Apoptotic processes may be implicated in the molecular pathomechanisms of ventricular remodeling after myocardial infarction (MI). The modulation of apoptosis by pro- and anti-apoptotic pathways in the myocardium remote from the infarction, including its link to protein kinase C (PKC), was focus of the present study. METHODS:Rats were subjected to MI by LAD ligation in situ. Some animals were pretreated with the PKC inhibitor chelerythrine. After 1 h up to 28 days, pro- and anti-apoptotic signals (caspase-3, Bcl-2/Bax ratio, Akt, Bad), and marker of apoptosis execution (DNA laddering, TUNEL) were quantified in the myocardium remote from the infarction. RESULTS: Activation of caspase-3, a pro-apoptotic shift of the Bcl-2/Bax ratio, and DNA fragmentation were observed as early as 3 h after infarction and persisted up to 28 days. Akt- and Bad-phosphorylation was unchanged. Chelerythrine markedly reduced DNA fragmentation. Caspase-3 activation was unchanged. Surprisingly, Bad and Akt phosphorylation were highly increased (180% and 750% of control). CONCLUSION:Chelerythrine influences the balance of pro- and anti-apoptotic pathways in the remote myocardium after infarction, with an inhibition of proapoptotic and an activation of anti-apoptotic signals.
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Authors: R H Strasser; G Simonis; S P Schön; M U Braun; R Ihl-Vahl; C Weinbrenner; R Marquetant; W Kübler Journal: Circ Res Date: 1999-07-09 Impact factor: 17.367
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