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

Roope K Sihvola, Ville P Pulkkinen, Petri K Koskinen, Karl B Lemström

Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland. Roope.Sihvola@Helsinki.Fi

Journal of the American College of Cardiology 2002 Feb 20

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

Citation

Roope K Sihvola, Ville P Pulkkinen, Petri K Koskinen, Karl B Lemström. Crosstalk of endothelin-1 and platelet-derived growth factor in cardiac allograft arteriosclerosis. Journal of the American College of Cardiology. 2002 Feb 20;39(4):710-7