Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes:: a role for p38 MAPK, Fas-L and cyclin D1

Background: Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fus-L, or through decreased expression of cyclin D, Aims. We tested the hypothesis that hypoxia (HX). angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK. and thus initiating stimulus specific changes in Fas-L and cyclin D, expression in failing cardiomyocytes. Methods and results: Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D, detection were performed. FIX-induced apoptosis was associated with increased Fas-L expression. A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D, expression. and NEPI-induced apoptosis was associated with decreased cyclin D, expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D, expression. Conclusions: FIX. A-II and NEPI mediate apoptosis in failing, cardiomyocytes via different effects on Fas-L and cyclin D, expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by FIX. A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D, (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.