title: Y-box binding protein-1 implicated in translational control of fetal myocardial gene expression after cardiac transplant.
abstract: Peri-transplant surgical trauma and ischemia/reperfusion injury in accepted murine heterotopic heart grafts has been associated with myofibroblast differentiation, cardiac fibrosis and biomechanical-stress activation of the fetal myocardial smooth muscle α-actin (SMαA) gene. The wound-healing agonists, transforming growth factor β1 and thrombin, are known to coordinate SMαA mRNA transcription and translation in activated myofibroblasts by altering the subcellular localization and mRNA-binding affinity of the Y-box binding protein-1 (YB-1) cold-shock domain (CSD) protein that governs a variety of cellular responses to metabolic stress. YB-1 accumulated in polyribosome-enriched regions of the sarcoplasm proximal to cardiac intercalated discs in accepted heart grafts. YB-1 binding to a purine-rich motif in exon 3 of SMαA mRNA that regulates translational efficiency increased substantially in perfusion-isolated, rod-shaped adult rat cardiomyocytes during phenotypic de-differentiation in the presence of serum-derived growth factors. Cardiomyocyte de-differentiation was accompanied by the loss of a 60 kDa YB-1 variant that was highly expressed in both adult myocardium and freshly isolated myocytes and replacement with the 50 kDa form of YB-1 (p50) typically expressed in myofibroblasts that demonstrated sequence-specific interaction with SMαA mRNA. Accumulation of p50 YB-1 in reprogrammed, de-differentiated myocytes was associated with a 10-fold increase in SMαA protein expression. Endomyocardial biopsies collected from patients up to 14 years after heart transplant showed variable yet coordinately elevated expression of SMαA and p50 YB-1 protein and demonstrable p50 YB-1:SMαA mRNA interaction. The p60 YB-1 variant in human heart graft samples, but neither mouse p60 nor mouse or human p50, reacted with an antibody specific for the phosphoserine 102 modification in the YB-1 CSD. Modulation of YB-1 subcellular compartmentalization and mRNA-binding activity may be linked with reprogramming of contractile protein gene expression in ventricular cardiomyocytes that could contribute to maladaptive remodeling in accepted, long-term heart grafts.
authors.affiliation: Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: David
authors.forename: Sukanya V
authors.initials: SV
authors.lastname: Subramanian
authors.forename: Aiwen
authors.initials: A
authors.lastname: Zhang
authors.forename: William L
authors.initials: WL
authors.lastname: Willis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Carl V
authors.initials: CV
authors.lastname: Leier
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Strauch
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D016027:Heart Transplantation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D016042:Transplantation, Heterotopic; D014945:Wound Healing; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D012333:RNA, Messenger; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C544013:alpha-smooth muscle actin, mouse