Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway

Koichiro Kamio, Xiang-de Liu, Hisatoshi Sugiura, Shinsaku Togo, Tetsu Kobayashi, Shinsaku Kawasaki, Xingqi Wang, Lijun Mao, Youngsoo Ann, Cory Hogaboam, Myron Lee Toews, Stephen I. Rennard

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Prostacyclin is an arachidonic acid metabolite that modulates vascular tone within the lung. The current study evaluated the hypothesis that prostacyclin can also modulate tissue remodeling by affecting fibroblast-mediated contraction of extracellular matrix. To accomplish this, fibroblasts were cultured in three-dimensional native type I collagen gels in the presence of prostacyclin analogs: carbaprostacyclin, iloprost, and beraprost. All three analogs significantly inhibited contraction of the three-dimensional collagen gels mediated by three different fibroblasts. All three analogs significantly inhibited fibronectin release and reduced fibroblast fibronectin mRNA expression. Addition of exogenous fibronectin restored the contractile activity to fibroblasts incubated in the presence of all three analogs. Iloprost and beraprost significantly activated cAMP-dependent protein kinase-A (PKA), and an action through this pathway was con firmed by blockade of the inhibitory effect on contraction and fibronectin release with the PKA inhibitor KT-5720. In contrast, carbaprostacyclin, which is not as selective for the prostacyclin (IP) receptor, did not activate PKA, and its effects on contraction and fibronectin release were not fully blocked by KT-5720. Finally, the cAMP analogs N 6 -Benzoyl- (6-Bnz-) cAMP and dibutyryl-cAMP inhibited contraction, and this contrasted with the activity of an Epac selective agonist 8-pCPT-2′-O-Me-cAMP, which had no effect. Taken together, these results indicate that prostacyclin, acting through the IP receptor and by activating PKA, can lead to inhibition of fibronectin release and can subsequently inhibit fibroblast-mediated collagen gel contraction. The ability of prostacyclin to modulate fibroblast function suggests that prostacyclin can contribute to tissue remodeling.

Original languageEnglish (US)
Pages (from-to)113-120
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume37
Issue number1
DOIs
StatePublished - Jul 1 2007

Fingerprint

Epoprostenol
Fibroblasts
Cyclic AMP-Dependent Protein Kinases
Fibronectins
Collagen
Gels
beraprost
Iloprost
Epoprostenol Receptors
Tissue
Protein Kinase Inhibitors
Metabolites
Collagen Type I
Arachidonic Acid
Extracellular Matrix
Blood Vessels
Lung
Messenger RNA

Keywords

  • Fibroblasts
  • Fibronectin
  • Prostacyclin
  • Tissue remodeling

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway. / Kamio, Koichiro; Liu, Xiang-de; Sugiura, Hisatoshi; Togo, Shinsaku; Kobayashi, Tetsu; Kawasaki, Shinsaku; Wang, Xingqi; Mao, Lijun; Ann, Youngsoo; Hogaboam, Cory; Toews, Myron Lee; Rennard, Stephen I.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 37, No. 1, 01.07.2007, p. 113-120.

Research output: Contribution to journalArticle

Kamio, K, Liu, X, Sugiura, H, Togo, S, Kobayashi, T, Kawasaki, S, Wang, X, Mao, L, Ann, Y, Hogaboam, C, Toews, ML & Rennard, SI 2007, 'Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway', American Journal of Respiratory Cell and Molecular Biology, vol. 37, no. 1, pp. 113-120. https://doi.org/10.1165/rcmb.2007-0009OC
Kamio, Koichiro ; Liu, Xiang-de ; Sugiura, Hisatoshi ; Togo, Shinsaku ; Kobayashi, Tetsu ; Kawasaki, Shinsaku ; Wang, Xingqi ; Mao, Lijun ; Ann, Youngsoo ; Hogaboam, Cory ; Toews, Myron Lee ; Rennard, Stephen I. / Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway. In: American Journal of Respiratory Cell and Molecular Biology. 2007 ; Vol. 37, No. 1. pp. 113-120.
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