title: Lactosylceramide promotes hypertrophy through ROS generation and activation of ERK1/2 in cardiomyocytes.
abstract: Hypertrophy is central to several heart diseases; however, not much is known about the role of glycosphingolipids (GSLs) in this phenotype. Since GSLs have been accorded several physiological functions, we sought to determine whether these compounds affect cardiac hypertrophy. By using a rat cardiomyoblast cell line, H9c2 cells and cultured primary neonatal rat cardiomyocytes, we have determined the effects of GSLs on hypertrophy. Our study comprises (a) measurement of [(3)H]-leucine incorporation into protein, (b) measurement of cell size and morphology by immunofluorescence microscopy and (c) real-time quantitative mRNA expression assay for atrial natriuretic peptide and brain natriuretic peptide. Phenylephrine (PE), a well-established agonist of cardiac hypertrophy, served as a positive control in these studies. Subsequently, mechanistic studies were performed to explore the involvement of various signaling transduction pathways that may contribute to hypertrophy in these cardiomyocytes. We observed that lactosylceramide specifically exerted a concentration- (50-100 µM) and time (48 h)-dependent increase in hypertrophy in cardiomyocytes but not a library of other structurally related GSLs. Further, in cardiomyocytes, LacCer generated reactive oxygen species, stimulated the phosphorylation of p44 mitogen activated protein kinase and protein kinase-C, and enhanced c-jun and c-fos expression, ultimately leading to hypertrophy. In summary, we report here that LacCer specifically induces hypertrophy in cardiomyocytes via an "oxygen-sensitive signal transduction pathway."
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Mishra
authors.forename: Subroto
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism* / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006028:Glycosphingolipids / Q000235:genetics / Q000378:metabolism*; D007790:Lactosylceramides / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D006028:Glycosphingolipids; D007790:Lactosylceramides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C009744:CDw17 antigen
keywords: cardiac hypertrophy; glycosphingolipids; lactosylceramide