title: Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts.
abstract: Platelet-derived growth factor (PDGF)-D is a newly recognized member of the PDGF family with its role just now being understood. Our previous study shows that PDGF-D and its receptors (PDGFR-β) are significantly increased in the infarcted heart, where PDGFR-β is primarily expressed by fibroblasts, indicating the involvement of PDGF-D in the development of cardiac fibrosis. In continuing with these findings, the current study explored the molecular basis of PDGF-D on fibrogenesis. Rat cardiac fibroblasts were isolated and treated with PDGF-D (200 ng/ml medium). The potential regulation of PDGF-D on fibroblast growth, phenotype change, collagen turnover, and the transforming growth factor (TGF)-β pathway were explored. We found: 1) PDGF-D significantly elevated cardiac fibroblast proliferation, myofibroblast (myoFb) differentiation, and type I collagen secretion; 2) matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 protein levels were significantly elevated in PDGF-D-treated cells, which were coincident with increased expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2; 3) PDGF-D significantly enhanced TGF-β1 synthesis, which was eliminated by TGF-β blockade with small-interfering RNA (siRNA); 4) the stimulatory role of PDGF-D on fibroblast proliferation and collagen synthesis was abolished by TGF-β blockade; and 5) TGF-β siRNA treatment significantly suppressed PDGF-D synthesis in fibroblasts. These observations indicate that PDGF-D promotes fibrogenesis through multiple mechanisms. Coelevations of TIMPs and MMPs counterbalance collagen degradation. The profibrogenic role of PDGF-D is mediated through activation of the TGF-β1 pathway. TGF-β1 exerts positive feedback on PDGF-D synthesis. These findings suggest the potential therapeutic effect of PDGFR blockade on interstitial fibrosis in the infarcted heart.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Li
authors.forename: Weixin
authors.initials: W
authors.lastname: Meng
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005246:Feedback; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D008666:Metalloendopeptidases
keywords: cardiac fibroblasts; collagen turnover; proliferation; transforming growth factor-β1