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J Am Coll Cardiol, 2002; 39:710-717
© 2002 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis

Roope K. Sihvola, MD*,*, Ville P. Pulkkinen, MSc*, Petri K. Koskinen, MD, PhD* and Karl B. Lemström, MD, PhD*

* Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland

Manuscript received February 7, 2001; revised manuscript received October 26, 2001, accepted November 13, 2001.

* Reprint requests and correspondence: Dr. Roope Sihvola, Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, P.O. Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Helsinki, Finland.
Roope.Sihvola{at}Helsinki.Fi

OBJECTIVES: In this study, we investigated the crosstalk of endothelin-1 (ET-1) and platelet-derived growth factor (PDGF) in coronary artery smooth muscle cell (SMC) proliferation in the rat cardiac allograft model.

BACKGROUND: Previous studies have suggested an independent role of ET-1 and PDGF in the development of cardiac allograft arteriosclerosis (i.e., chronic rejection).

METHODS: Heterotopic heart transplantations were performed from Dark Agouti to Wistar Furth rats. Grafts were harvested after five days in an acute rejection model and after 60 days in a chronic rejection model. In the in vitro part of the study, SMC proliferation and migration were quantitated, as well as messenger ribonucleic acid (mRNA) levels of ET-1 and PDGF ligands and receptors after growth factor stimulation.

RESULTS: Acute rejection induced both ET-1 receptors in the arterial wall. On linear regression analysis of chronically rejecting cardiac allografts, a strong correlation between intimal thickening and immunoreactivity of ET-1 and ET receptors A and B (ETA and ETB) in the arterial walls was observed. Treatment with Bosentan, a mixed ET-1 receptor antagonist, significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac allografts, as well as total intragraft ETA and ETB mRNA expression and intimal cell ET-1 and receptor immunoreactivity. This was associated with significantly reduced intragraft PDGF beta-receptor (PDGF-Rbeta) mRNA expression. In contrast, CGP 53716, a protein tyrosine kinase inhibitor selective for the PDGF receptor, did not reduce intragraft ET-1, ETA or ETB mRNA expression. In rat coronary artery SMC cultures, ET-1 stimulation significantly upregulated PDGF-Ralpha and -Rbeta mRNA expression and augmented PDGF-BB–mediated SMC proliferation as well as PDGF-AB– and PDGF-BB–mediated SMC migration.

CONCLUSIONS: Our results suggest that the ET-1/PDGF-Rbeta/PDGF-BB axis may operate in SMC migration and proliferation in cardiac allograft arteriosclerosis, thus explaining the marked beneficial effects of blocking the signaling downstream of ET-1 receptors.

Abbreviations and Acronyms
  RT-PCR
  CsA
  cyclosporin A
  DMEM
  Dulbecco’s Modified Eagle Medium
  EC
  endothelial cell
  ET
  endothelin
  FBS
  fetal bovine serum
  IL
  interleukin
  mRNA
  messenger ribonucleic acid
  PDGF
  platelet-derived growth factor
  RT-PCR
  reverse transcription polymerase chain reaction
  SMC
  smooth muscle cell
  TNF
  tumor necrosis factor




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