title: Reprogramming of vascular smooth muscle alpha-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant.
abstract: OBJECTIVE
  Chronic rejection in cardiac allografts depletes vascular smooth muscle (VSM) alpha-actin from the coronary arterial smooth muscle bed while promoting its abnormal accumulation in cardiomyocytes and myofibroblasts. The objective was to determine if the newly discovered TEF1, MSY1, Puralpha and Purbeta VSM alpha-actin transcriptional reprogramming proteins (TRPs) were associated with development of chronic rejection histopathology in accepted murine cardiac allografts.
  
  
  METHODS
  A mouse heterotopic cardiac transplant model was employed using H2 locus-mismatched mouse strains (DBA/2 or FVB/N to C57BL/6). Recipients were immunosuppressed to promote long-term allograft acceptance and emergence of chronic rejection. Explanted grafts and isolated heart cells were evaluated for changes in the DNA-binding activity and subcellular distribution of VSM alpha-actin transcriptional regulatory proteins.
  
  
  RESULTS
  The DNA-binding activity of all four TRPs was high in the developing mouse ventricle, minimal in adult donor hearts and increased substantially within 30 days after transplantation. Immunohistologic analysis revealed nuclear localization of Purbeta and MSY1 particularly in fibrotic areas of the allograft myocardium demonstrating extravascular accumulation of VSM alpha-actin. Cardiomyocytes isolated from adult, non-transplanted mouse hearts not only exhibited less VSM alpha-actin expression and lower levels of TRPs compared to isolated cardiac fibroblasts or neonatal cardiomyocytes, but also contained a novel size variant of the MSY1 protein.
  
  
  CONCLUSIONS
  Accumulation of TRPs in cardiac allografts, particularly within the fibroblast-enriched myocardial interstitium, was consistent with their potential role in VSM alpha-actin gene reprogramming, fibrosis and dysfunctional remodeling following transplant. These nuclear protein markers could help stage peri-transplant cellular events that precede formation of graft-destructive fibrosis and coronary vasculopathy during chronic rejection.
authors.affiliation: Department of Physiology and Cell Biology and the Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA.
authors.forename: Sukanya V
authors.initials: SV
authors.lastname: Subramanian
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: John A
authors.initials: JA
authors.lastname: Polikandriotis
authors.forename: Charles G
authors.initials: CG
authors.lastname: Orosz
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Strauch
mesh_terms: D000199:Actins / Q000235:genetics*; D000818:Animals; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D005809:Genes, Regulator; D005819:Genetic Markers; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology; D016027:Heart Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins; D020648:Peptide Elongation Factor 1 / Q000032:analysis / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014184:Transplantation, Homologous
chemical_list: D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D020648:Peptide Elongation Factor 1; D014157:Transcription Factors; C121485:Pura protein, mouse; C108770:Purb protein, mouse; C541744:Ybx1 protein, mouse