Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts

Tieqiang Zhao, Wenyuan Zhao, Yuanjian Chen, Victoria S. Li, Weixin Meng, Yao Sun

Research output: Contribution to journalArticle

33 Citations (Scopus)

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-Dtreated 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-βblockade 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.

Original languageEnglish (US)
Pages (from-to)H1719-H1726
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number12
DOIs
StatePublished - Jun 25 2013

Fingerprint

Platelet-Derived Growth Factor
Fibroblasts
Transforming Growth Factors
Collagen
Small Interfering RNA
Fibrosis
Tissue Inhibitor of Metalloproteinase-3
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Myofibroblasts
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Therapeutic Uses
Collagen Type I
Matrix Metalloproteinases

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts. / Zhao, Tieqiang; Zhao, Wenyuan; Chen, Yuanjian; Li, Victoria S.; Meng, Weixin; Sun, Yao.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 304, No. 12, 25.06.2013, p. H1719-H1726.

Research output: Contribution to journalArticle

Zhao, Tieqiang ; Zhao, Wenyuan ; Chen, Yuanjian ; Li, Victoria S. ; Meng, Weixin ; Sun, Yao. / Platelet-derived growth factor-D promotes fibrogenesis of cardiac fibroblasts. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 304, No. 12. pp. H1719-H1726.
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