Palmitate alters neuregulin signaling and biology in cardiac myocytes

The saturated fatty acid palmitate alters normal cell function via disruption of cell signaling, and this effect has been implicated in the end-organ damage associated with dyslipidemia. Neuregulin-1beta (NRG-1beta) is a growth and survival factor in cardiac myocytes. We tested the hypothesis that palmitate alters NRG-1beta signaling and biology in isolated neonatal rat cardiac myocytes. Palmitate treatment inhibited NRG-1beta activation of the PI3-kinase/Akt pathway in myocytes. We found that the pro-apoptotic activity of palmitate was increased by NRG-1beta treatment. The effects of palmitate on NRG-1beta signaling and survival were reversed by the mono-unsaturated fatty acid oleate. Under control conditions NRG-1beta decreases p53 expression in myocytes. In the presence of palmitate, NRG-1beta caused an increase in p53 expression, bax multimer formation, concurrent with degradation of mdm2, a negative regulator of p53. Thus in the presence of palmitate NRG-1beta activates pro-apoptotic, rather than pro-survival signaling in cardiac myocytes.