P38α MAPK mediates saturated fatty acid‐induced cardiomyocyte apoptosis (547.19)

Abstract

Listen

Translate article

BACKGROUND: Cardiomyocyte apoptosis mediated by a p38α MAPK‐dependent pathway may be a key step leading to lipotoxic/diabetic cardiomyopathy. Saturated fatty acid (SFA), elevated in type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. We tested the hypothesis that SFA‐induced cardiomyocyte apoptosis is dependent on p38α activation.METHODS AND RESULTS: Immortalized human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of a SFA, palmitate (PA). The apoptotic response was determined by flow cytometry, and the p38α‐dependent pathway evaluated using a p38 inhibitor, and by p38α siRNA knockdown.PA increased apoptosis in AC16 cardiomyocytes dose‐dependently; after 16 h exposure to PA (control‐2.6±0.7%, 150 μM PA‐3.5±1.1%, 300 μM PA‐11.5±3.4%, n=4, p<0.001). Apoptosis rose higher after 24 h treatment (control‐2.3±0.7%, 150 μM PA‐5.9±2.7%, 300 μM PA‐37.6±10.7%, n=3, p<0.02).PA did not change total p38α protein levels, but increased p38α phosphorylation. Specific p38α siRNA reduced the expression of p38α but not p38β, and markedly 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<0.04). PD169316, which inhibits both p38α and p38β isoforms, tended to reduce PA‐induced apoptosis (n=4, p=0.05).Downstream, AP‐1 transcription factors, c‐fos and c‐jun (n=3, p蠄0.05), and caspase 8 (n=3, p=0.03) mRNA levels, and protein expression were increased by PA. CONCLUSIONS: This study in cardiomyocytes demonstrated that 1) PA induces p38α activation, 2) PA increases AP‐1 and caspase 8 expression, and 3) reduced p38α expression attenuates PA‐induced apoptosis. Weaker results with PD169316 may be due to concurrent inhibition of p38β. Our results suggest a potential mechanism by which high plasma SFA levels may lead to the development of diabetic cardiomyopathy.Grant Funding Source: VA