Caveolin-1 expression by means of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide.
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.
Kim
Hong Pyo
HP
Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Wang
Xue
X
Nakao
Atsunori
A
Kim
Sung Il
SI
Murase
Noriko
N
Choi
Mary E
ME
Ryter
Stefan W
SW
Choi
Augustine M K
AM
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
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