title: Palmitate alters neuregulin signaling and biology in cardiac myocytes.
abstract: 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.
authors.affiliation: Boston University School of Medicine, Department of Medicine, Boston, MA, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cote
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Lebrasseur
authors.forename: Steve C
authors.initials: SC
authors.lastname: Borkan
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Xuyang
authors.initials: X
authors.lastname: Peng
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D020890:Neuregulin-1; D010168:Palmitates / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D010168:Palmitates; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt