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Hypoxia, angiotensin‐II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas‐L and cyclin D 1

2003; Elsevier BV; Volume: 5; Issue: 2 Linguagem: Inglês

10.1016/s1388-9842(02)00254-4

1879-0844

Victor G. Sharov, Anastassia Todor, George Suzuki, Hideaki Morita, Elaine J. Tanhehco, Hani N. Sabbah,

Autophagy in Disease and Therapy

Abstract 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 Fas‐L, or through decreased expression of cyclin D 1 . 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 1 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 1 detection were performed. HX‐induced apoptosis was associated with increased Fas‐L expression, A‐II‐induced apoptosis was associated with increased Fas‐L and decreased cyclin D 1 expression, and NEPI‐induced apoptosis was associated with decreased cyclin D 1 expression. Inhibition of p38 MAPK activity attenuated stress‐induced apoptosis in all experiments and reversed changes in Fas‐L and cyclin D 1 expression. Conclusions: HX, A‐II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas‐L and cyclin D 1 expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A‐II and NEPI involves activation of p38 MAPK upstream from Fas‐L and cyclin D 1 .