Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway.
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 confirmed 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.
Kamio
Koichiro
K
University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885, USA.
Liu
Xiangde
X
Sugiura
Hisatoshi
H
Togo
Shinsaku
S
Kobayashi
Tetsu
T
Kawasaki
Shinsaku
S
Wang
Xingqi
X
Mao
Lijun
L
Ahn
Youngsoo
Y
Hogaboam
Cory
C
Toews
Myron L
ML
Rennard
Stephen I
SI
D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005782:Gels; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology
D002227:Carbazoles; D005353:Fibronectins; D005782:Gels; D007211:Indoles; D011758:Pyrroles; C057416:KT 5720; D003094:Collagen; D011464:Epoprostenol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases