Journal
EUROPEAN JOURNAL OF HEART FAILURE
Volume 5, Issue 2, Pages 121-129Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S1388-9842(02)00254-4
Keywords
heart failure; p38 MAPK; apoptosis; Fas-L; cyclin D-1
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Funding
- NHLBI NIH HHS [HL-49090-07] Funding Source: Medline
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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.
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