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

Abstract

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.

• Authors: Roope K Sihvola, Ville P Pulkkinen, Petri K Koskinen, Karl B Lemström
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 39 Issue 4 Pg. 710-7 (Feb 20 2002) ISSN: 0735-1097 [Print] United States
• PMID: 11849873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Platelet-Derived Growth Factor

Topics

• Animals
• Cell Culture Techniques
• Coronary Artery Disease (pathology, physiopathology)
• Coronary Vessels (pathology, physiopathology)
• Disease Models, Animal
• Endothelin-1 (physiology)
• Graft Rejection (pathology, physiopathology)
• Heart Transplantation (pathology, physiology)
• Muscle, Smooth, Vascular (pathology, physiopathology)
• Platelet-Derived Growth Factor (physiology)
• Rats
• Rats, Inbred Strains
• Rats, Inbred WF
• Receptor Cross-Talk (physiology)
• Transplantation, Homologous (pathology, physiology)