title: Inhibition of anti-apoptotic signals by Wortmannin induces apoptosis in the remote myocardium after LAD ligation: evidence for a protein kinase C-δ-dependent pathway.
abstract: It has been shown that, in the remote myocardium after infarction (MI), protein kinase C (PKC) inhibition reduces apoptosis both by blocking proapoptotic pathways and by activating antiapoptotic signals including the Akt pathway. However, it was open if vice versa, blockade of antiapoptotic pathways may influence proapoptotic signals. To clarify this, the present study tested the effects of the PI3-kinase blocker Wortmannin on proapoptotic signals and on apoptosis execution in the remote myocardium after infarction. Rats were subjected to MI by LAD ligation in situ. Some were pre-treated with Wortmannin alone or in combination with the PKC inhibitor Chelerythrine. After 24 h, pro- and anti-apoptotic signals (caspase-3, PKC isoforms, p38-MAPK, p42/44-MAPK, Akt, Bad), and marker of apoptosis execution (TUNEL) were quantified in the myocardium remote from the infarction. Wortmannin treatment increased apoptosis in the remote myocardium both at baseline and after MI, together with an activation of the PKC-δ/p38-MAPK-pathway. PKC-ε and p42/44-MAPK were unaffected. Combined treatment with Wortmannin and Chelerythrine fully reversed the pro-apoptotic effects of Wortmannin both at baseline and after MI. The PKC-δ-p38-MAPK-pathway as a strong signal for apoptosis in the non-infarcted myocardium can be influenced by targeting the anti-apoptotic PI3-kinase pathway. This gives evidence of a bi-directional crosstalk of pro- and anti-apoptotic signals after infarction.
authors.affiliation: Department of Medicine/Cardiology, Heart Center Dresden, University Hospital, Dresden University of Technology, Fetscherstrasse 76, 01307 Dresden, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wiedemann
authors.forename: Teresa
authors.initials: T
authors.lastname: Wessela
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Dirk
authors.initials: D
authors.lastname: Joachim
authors.forename: Marcel
authors.initials: M
authors.lastname: Jercke
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.forename: Bernd
authors.initials: B
authors.lastname: Ebner
authors.forename: Gregor
authors.initials: G
authors.lastname: Simonis
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D009320:Atrial Natriuretic Factor / Q000097:blood*; D053119:Benzophenanthridines / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D004790:Enzyme Induction; D000077405:Irbesartan; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000097:blood; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D011498:Protein Precursors / Q000097:blood*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D009320:Atrial Natriuretic Factor; D053119:Benzophenanthridines; D001713:Biphenyl Compounds; D053148:Caspase 3; D000077405:Irbesartan; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D011498:Protein Precursors; D013777:Tetrazoles; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C016299:chelerythrine; C497257:Prkce protein, rat; C505410:Casp3 protein, rat