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Biochemical and biophysical research communications

p38α mitogen-activated kinase mediates cardiomyocyte apoptosis induced by palmitate.


PMID 24931668

Abstract

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. We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation. 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). 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.