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

Abstract

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-beta1 pathway. Inhibition of signaling of all PDGF-ligands except that of PDGF-B may thus be needed to inhibit chronic rejection in cardiac allografts.

Imatinib Mesylate Attenuates Myocardial Remodeling Through Inhibition of Platelet-Derived Growth Factor and Transforming Growth Factor Activation in a Rat Model of Hypertension

“…23,24 C-abl is also a novel mediator of TGF-β1-induced fibroblast growth, morphological transformation, and matrix gene expression. 10,13 PDGF upregulates the expression of TGF-β1 in a rat cardiac allograft 25 and c-abl in fibroblast. 26 In addition, PDGF also directly stimulates fibroblasts to contract collagen matrices and differentiate into myofibroblasts.…”

Potential Therapeutic Targets for Cardiac Fibrosis

“…PDGF␣ receptor mRNA is upregulated in acutely rejecting cardiac allografts, and PDGF-A and PDGF-C mRNAs are upregulated in chronically rejecting cardiac allografts. 67 PDGF-A, PDGF-C, or PDGF-D, when introduced into the heart using adenovirusmediated delivery, significantly upregulated profibrotic TGF␤1 mRNA and accelerated cardiac fibrosis and arteriosclerosis, indicating that PDGF may also act to promote fibrosis by elevating TGF␤ levels. 67 Atrial fibrillation, characterized by atrial fibrosis, is a common arrhythmia that increases the risk of stroke and heart failure.…”

“…67 PDGF-A, PDGF-C, or PDGF-D, when introduced into the heart using adenovirusmediated delivery, significantly upregulated profibrotic TGF␤1 mRNA and accelerated cardiac fibrosis and arteriosclerosis, indicating that PDGF may also act to promote fibrosis by elevating TGF␤ levels. 67 Atrial fibrillation, characterized by atrial fibrosis, is a common arrhythmia that increases the risk of stroke and heart failure. Injection of neutralizing PDGF␣ receptor-specific antibody attenuated atrial fibrosis.…”

Getting to the Heart of the Matter

“…91 Similarly, PDGF-A, PDGF-C, or PDGF-D, when introduced into the heart using adenovirus-mediated delivery, significantly upregulated TGF-β1 mRNA expression and also accelerated cardiac fibrosis and arteriosclerosis. 92 Collectively, these data indicate that PDGF may promote fibrosis by elevating TGF-β levels. These results strongly suggest that PGDF may be a good target for antifibrotic therapy in the heart; however, given the complexity of the molecules involved with the PDGF signaling pathway, developing antifibrotic agents against this pathway may be difficult.…”