Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase

Cecilia Berg; Sven Hammarström; Helena Herbertsson; Eva Lindström; Ann-Charlotte Svensson; Mats Söderström; Pentti Tengvall; Torbjörn Bengtsson

doi:10.1160/TH06-02-0069

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(05): 652-659
DOI: 10.1160/TH06-02-0069

Wound Healing and Inflammation/Infection

Schattauer GmbH

Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase

Authors

Cecilia Berg

¹Division of Pharmacology, Department of Medicine and Care, Linköping, Sweden
Sven Hammarström

²Division of Cell Biology, Department of Biomedicine and Surgery, Linköping, Sweden
Helena Herbertsson

³Division of Chemistry, Cardiovascular Inflammation Research Center, Linköping, Sweden
Eva Lindström

¹Division of Pharmacology, Department of Medicine and Care, Linköping, Sweden
Ann-Charlotte Svensson

¹Division of Pharmacology, Department of Medicine and Care, Linköping, Sweden
Mats Söderström

²Division of Cell Biology, Department of Biomedicine and Surgery, Linköping, Sweden
Pentti Tengvall

⁴Materials in Medicine, Division of Applied Physics, Department of Physics, Chemistry and Biology; Linköping University, Linköping, Sweden
Torbjörn Bengtsson

¹Division of Pharmacology, Department of Medicine and Care, Linköping, Sweden

Abstract

Summary

Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A₂ inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1–2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis.

Keywords

Fibroblasts - platelets - proliferation - 5-lipoxygenase - atherosclerosis

Full Text

References

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