Chelerythrine treatment influences the balance of pro- and anti-apoptotic signaling pathways in the remote myocardium after infarction.
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).


CONCLUSIONS
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.
Department of Medicine and Cardiology, Dresden University of Technology, Fetscherstr. 76, 01307 Dresden, Germany. gsimonis@gmx.de
Gregor
G
Simonis
Stephan
S
Wiedemann
Kerstin
K
Schwarz
Torsten
T
Christ
Daniel G
DG
Sedding
Xinjian
X
Yu
Rainer
R
Marquetant
Ruediger C
RC
Braun-Dullaeus
Ursula
U
Ravens
Ruth H
RH
Strasser
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000097:blood; D053119:Benzophenanthridines / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D053119:Benzophenanthridines; D015415:Biomarkers; D051025:bcl-Associated Death Protein; D009320:Atrial Natriuretic Factor; C016299:chelerythrine; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta