PDGF-A, -C, and -D but not PDGF-B Increase TGF-β1 and Chronic Rejection in Rat Cardiac Allografts

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 29; no. 5; pp. 691 - 698
• Main Authors: TUUMINEN, Raimo, NYKÄNEN, Antti I, KREBS, Rainer, SORONEN, Jarkko, PAJUSOLA, Katri, KERÄNEN, Mikko A. I, KOSKINEN, Petri K, ALITALO, Kari, LEMSTRÖM, Karl B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott Williams & Wilkins 01-05-2009
• Subjects: Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrinopathies; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Thyroid. Thyroid axis (diseases); Graft(material); smooth muscle cell; Rat; gene transfer; Rodentia; Smooth muscle; Cardiovascular disease; Homotransplantation; Vascular disease; Rejection; Vertebrata; Chronic; arteriosclerosis; Mammalia; Animal; Atherosclerosis; Fibrosis; transplantation
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.108.178558

Objective—
Chronic rejection is the main reason for the poor long-term survival of heart transplant recipients and is characterized by cardiac allograft inflammation, fibrosis, and arteriosclerosis. We examined the specific roles of different platelet-derived growth factor (PDGF) ligands (A–D)—potent mesenchymal cell mitogens—in rat cardiac allografts.
Methods and Results—
PDGFR-α mRNA was upregulated in acutely-rejecting, and PDGF-A and PDGF-C mRNA in chronically-rejecting cardiac¢hatn allografts. In acute rejection, PDGFR-α immunoreactivity increased in the media of arteries. In chronically-rejecting allografts, immunoreactivity of all PDGF ligands and receptors—except that of PDGF-B ligand—was found in the intima of arteries, and the expression of PDGF-A and PDGF-C was seen in cardiomyocytes. Intracoronary adeno-associated virus-2 (AAV2)-mediated PDGF-A and -D gene transfer enhanced cardiac allograft inflammation. AAV2-PDGF-A, AAV2-PDGF-C, and AAV2-PDGF-D significantly upregulated profibrotic TGF-β1 mRNA and accelerated cardiac fibrosis and arteriosclerosis. In contrast, AAV2-PDGF-B did not aggravate chronic rejection.
Conclusions—
We found that alloimmune response induces PDGF-A, PDGF-C, and PDGF-D expression in the graft vasculature. PDGF-A, PDGF-C, and PDGF-D mediated profibrotic and proarteriosclerotic effects in transplanted hearts involving the TGF-β1 pathway. Inhibition of signaling of all PDGF-ligands except that of PDGF-B may thus be needed to inhibit chronic rejection in cardiac allografts.
Alloimmune response induces PDGF-A, PDGF-C, and PDGF-D in the graft vasculature, and overexpression of these ligands upregulates TGF-β1 mRNA and enhances cardiac fibrosis and arteriosclerotic changes in cardiac allografts. Our results suggest that inhibition of signaling of all PDGF ligands except that of PDGF-B may be needed to inhibit chronic rejection in cardiac allografts.