title: Association of thrombospondin-1 and cardiac allograft vasculopathy in human cardiac allografts.
abstract: BACKGROUND
  Despite the expression of angiogenic growth factors in transplanted hearts, neovessel formation appears scant. We therefore hypothesized that cardiac allografts contain endogenous inhibitors of angiogenesis. In particular, we tested the involvement in cardiac allografts of thrombospondin-1 (TSP-1), a matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell (SMC) proliferation.
  
  
  RESULTS
  Levels of TSP-1 mRNA in endomyocardial biopsy samples of human cardiac allografts substantially exceeded those in normal hearts. The ratio of TSP to GAPDH mRNA determined with quantitative RT-PCR was 6.54+/-1.6 in cardiac allografts versus 0.26+/-0.02 (P:=0.001) in normal hearts. Analysis in sequential biopsies revealed a strong association between persistent elevation of TSP-1 in allografts and the development of cardiac allograft vasculopathy (CAV). The CAV score was 2.4+/-0.8 in patients with persistent TSP-1 elevation compared with 0.2+/-0.2 in patients without elevation (P:=0.001). Immunohistochemistry demonstrated intense expression of TSP-1 in cardiac allografts, predominantly in cardiac myocytes and neointimal SMCs. In vitro experiments demonstrated that T cells expressed TSP-1, acidic fibroblast growth factor, and vascular endothelial cell growth factor on allogeneic stimulation. Cytokines known to be elevated in cardiac allografts (interleukin-1beta, interferon-gamma, and tumor necrosis factor-alpha) induced TSP-1 in SMCs but inhibited TSP-1 in endothelial cells.
  
  
  CONCLUSIONS
  Persistent elevation of TSP-1 in cardiac allografts correlates with the development of CAV. Allogeneic stimulation induces angiogenic growth factors and TSP-1 in T cells. Cytokines differentially regulate TSP-1 expression in SMCs versus endothelial cells. Increased levels of TSP-1 in human cardiac allografts may alter vascular responses to angiogenic growth factors by inhibiting angiogenesis and promoting SMC proliferation characteristic of CAV.
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: X M
authors.initials: XM
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: G G
authors.initials: GG
authors.lastname: Miller
authors.forename: R N
authors.initials: RN
authors.lastname: Mitchell
authors.forename: P
authors.initials: P
authors.lastname: Libby
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology / Q000235:genetics*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D018955:CD36 Antigens; D016207:Cytokines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016220:Fibroblast Growth Factor 1