title: Caveolin-1 expression by means of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide.
abstract: During vascular injury, the proliferation and migration of smooth muscle cells leads to characteristic neointima formation, which can be exacerbated by genetic depletion of caveolin-1 or heme oxygenase 1 (HO-1), and inhibited by carbon monoxide (CO), a by-product of heme oxygenase 1 activity. CO inhibited smooth muscle cell proliferation by activating p38 mitogen-activated protein kinase (MAPK) and p21(Waf1/Cip1). Exposure to CO increased caveolin-1 expression in neointimal lesions of injured aorta and in vitro by activating guanylyl cyclase and p38 MAPK. p38beta-/- fibroblasts did not induce caveolin-1 in response to CO, and exhibited a diminished basal caveolin-1 expression, which was restored by p38beta gene transfer. p38beta MAPK down-regulated extracellular signal-regulated protein kinase 1/2 (ERK-1/2), which can repress caveolin-1 transcription. Genetic depletion of caveolin-1 abolished the antiproliferative effect of CO. Thus, we demonstrate that CO, by activating p38beta MAPK, up-regulates caveolin-1, which acts as a tumor suppressor protein that mediates the growth inhibitory properties of this gas.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Kim
authors.forename: Noriko
authors.initials: N
authors.lastname: Murase
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D001011:Aorta / Q000293:injuries* / Q000378:metabolism; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013936:Thymidine; D014316:Tritium
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D014316:Tritium; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D048290:Mitogen-Activated Protein Kinase 11; D006162:Guanylate Cyclase; D013936:Thymidine