This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sihvola, R. K. Articles by Lemström, K. B. Search for Related Content PubMed PubMed Citation Articles by Sihvola, R. K. Articles by Lemström, K. B.

EXPERIMENTAL STUDY

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

^* 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 (ET_A and ET_B) 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 ET_A and ET_B 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, ET_A or ET_B 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

This article has been cited by other articles:

				M. Takahashi The role of endothelin-1 in vascular remodeling in vivo Cardiovasc Res, July 1, 2006; 71(1): 4 - 5. [Full Text] [PDF]

				R. S. Poston, J. Gu, D. Prastein, F. Gage, J. W. Hoffman, M. Kwon, A. Azimzadeh, R. N. Pierson III, and B. P. Griffith Optimizing Donor Heart Outcome After Prolonged Storage With Endothelial Function Analysis and Continuous Perfusion Ann. Thorac. Surg., October 1, 2004; 78(4): 1362 - 1370. [Abstract] [Full Text] [PDF]