Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid
| Autor: | Charles C. Oh, John D. Lee, Kent L. Thornburg, Peter D. Reaven, Raymond Q. Migrino, Weiyang Zhang, Karen M. D'Souza |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Programmed cell death Small interfering RNA Transcription Genetic Proto-Oncogene Proteins c-jun Clinical Biochemistry Palmitic Acid Pharmaceutical Science Apoptosis Caspase 8 Mitogen-Activated Protein Kinase 14 03 medical and health sciences 0302 clinical medicine Mitogen-Activated Protein Kinase 11 Humans Myocytes Cardiac Phosphorylation RNA Small Interfering Cell Line Transformed Pharmacology biology Chemistry Biochemistry (medical) Cell Biology Caspase Inhibitors Cell biology Transcription Factor AP-1 030104 developmental biology 030220 oncology & carcinogenesis Mitogen-activated protein kinase Saturated fatty acid biology.protein Proto-Oncogene Proteins c-fos |
| Zdroj: | Apoptosis : an international journal on programmed cell death. 24(5-6) |
| ISSN: | 1573-675X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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