P38α mitogen-activated kinase mediates cardiomyocyte apoptosis induced by palmitate

Charles C. Oh, Michael Q. Nguy, Dawn C. Schwenke, Raymond Q. Migrino, Kent Thornburg, Peter Reaven

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    Abstract

    Rationale The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38α mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults. Objective We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation. Methods and results Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38α-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38α small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6 ± 0.6%, 150 μM PA: 3.5 ± 0.9%, 300 μM PA: 11.5 ± 1.6%, n = 4, p < 0.01). PA did not change total p38α protein levels, but increased p38α phosphorylation dose-dependently (n = 5, p < 0.01). PD169316 tended to reduce PA-induced apoptosis (n = 4, p = 0.05). Specific p38α siRNA markedly reduced the expression of p38α but not p38β (n = 3, p < 0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7 ± 1.0%, 300 μM PA: 34.4 ± 5.0%, 300 μM PA + 30 pmol siRNA: 23.7 ± 4.4%, 300 μM PA + 60 pmol siRNA: 19.7 ± 2.6%, 300 μM PA + 120 pmol siRNA: 17.3 ± 2.8%, n = 4, p < 0.0001). Conclusions These results demonstrate that PA induces p38α activation, and reducing p38α expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38α activation may lead to the development of lipotoxic/diabetic cardiomyopathy.

    Original languageEnglish (US)
    Pages (from-to)628-633
    Number of pages6
    JournalBiochemical and Biophysical Research Communications
    Volume450
    Issue number1
    DOIs
    StatePublished - Jul 18 2014

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    Keywords

    • Apoptosis
    • Cardiomyopathy
    • Diabetes
    • Lipotoxic
    • p38α MAPK

    ASJC Scopus subject areas

    • Biophysics
    • Biochemistry
    • Molecular Biology
    • Cell Biology

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