Heme Oxygenase Inhibits Human Airway Smooth Muscle Proliferation via a Bilirubin-dependent Modulation of ERK1/2 Phosphorylation
| Autor: | Jorge Boczkowski, Elie Fadel, Tokio Yamaguchi, Michel Aubier, Patrick Berger, Camille Taillé, Roger Marthan, Guy Lesèche, Christine Zedda, Abdelhamid Almolki, Moussa Benhamed, Jérôme Mégret |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Ovalbumin
medicine.medical_treatment Guinea Pigs Biochemistry Oligodeoxyribonucleotides Antisense chemistry.chemical_compound In vivo Extracellular medicine Animals Humans Phosphorylation Molecular Biology Cells Cultured Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Base Sequence biology Cell growth Growth factor Membrane Proteins Bilirubin Cell Biology Molecular biology Asthma Respiratory Muscles Heme oxygenase chemistry Heme Oxygenase (Decyclizing) biology.protein Immunization Mitogen-Activated Protein Kinases Reactive Oxygen Species Oxidation-Reduction Cell Division Heme Oxygenase-1 Hemin |
| Zdroj: | Journal of Biological Chemistry. 278:27160-27168 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m300364200 |
| Popis: | The aim of this study was to investigate whether the heme oxygenase (HO) pathway could modulate proliferation of airway smooth muscle (ASM) and the mechanism(s) involved in this phenomenon. In cultured human ASM cells, 10% fetal calf serum or 50 ng/ml platelet-derived growth factor AB induced cell proliferation, extracellular and intracellular reactive oxygen species (ROS) production and ERK1/2 phosphorylation. Pharmacological HO-1 induction (by 10 microm hemin or by 20 microm cobalt-protoporphyrin) and HO inhibition (by 25 microm tin-protoporphyrin or by an antisense oligonucleotide), respectively, reduced and enhanced significantly both cell proliferation and ROS production. Neither the carbon monoxide scavenger myoglobin (5-20 microm) nor the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one could reverse ASM proliferation induced by tin-protoporphyrin, making a role of the CO-cGMP pathway in HO-modulated proliferation unlikely. By contrast, bilirubin (1 microm) and the antioxidant N-acetyl-cysteine (1 mm) significantly reduced mitogen-induced cell proliferation, ROS production, and ERK1/2 phosphorylation. Furthermore, both bilirubin and N-acetyl-cysteine and the ERK1/2 inhibitor PD98059 significantly reversed the effects of HO inhibition on ASM proliferation. These results could be relevant to ASM alterations observed in asthma because activation of the HO pathway prevented the increase in bronchial smooth muscle area induced by repeated ovalbumin challenge in immunized guinea pigs, whereas inhibition of HO had the opposite effect. In conclusion, this study provides evidence for an antiproliferative effect of the HO pathway in ASM in vitro and in vivo through a bilirubin-mediated redox modulation of phosphorylation of ERK1/2. |
| Databáze: | OpenAIRE |
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