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Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid

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Abstract

Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.

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Funding

This work has been funded by VA VISN 18 New Investigator Grant (to C.O.), CSR&D 5I01CX000598 grant (to P.R.), and VA Merit Grant BLRD I01BX007080 (to R.M.). The study was supported by VA Employment and Carl T. Hayden Medical Research Foundation. The contents and the views do not represent the views of the Department of Veterans Affairs or the US government. K.T. is supported by the M. Lowell Edwards Endowment.

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Authors and Affiliations

  1. Cardiology Division, Phoenix VA Healthcare System, 650 E Indian School Rd, 111F, Phoenix, USA

    Charles C. Oh

  2. Norton Thoracic Institute, Phoenix, USA

    John Lee

  3. Carl T Hayden Research Foundation, Phoenix, USA

    Karen D’Souza

  4. Oregon Health and Science University, Portland, USA

    Kent Thornburg

  5. Phoenix VA Healthcare System, Phoenix, USA

    Weiyang Zhang, Raymond Q. Migrino & Peter Reaven

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  1. Charles C. Oh
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  2. John Lee
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  3. Karen D’Souza
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  4. Weiyang Zhang
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  5. Raymond Q. Migrino
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  6. Kent Thornburg
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  7. Peter Reaven
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Correspondence to Charles C. Oh.

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Oh, C.C., Lee, J., D’Souza, K. et al. Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid. Apoptosis 24, 395–403 (2019). https://doi.org/10.1007/s10495-018-01510-y

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  • DOI: https://doi.org/10.1007/s10495-018-01510-y

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