11713104

pubmed:Citation

5

Pulmonary fibrosis is a progressive disorder characterized by the loss of alveolar architecture through epithelial and endothelial cell apoptosis and fibroblast proliferation. Recent studies showed that angiotensin-converting enzyme (ACE) activity is increased in fibrotic tissues, and ACE inhibitors administered in vivo ameliorate fibrosis, suggesting that ACE may play a critical role. However, the regulation of ACE expression is not well understood. In the present study, we demonstrate that bleomycin, a chemotherapeutic agent which induces pulmonary fibrosis in animals and humans, increases gene expression of ACE. Treatment of primary bovine pulmonary artery endothelial cells with 0.1 to 1.0 microg/ml bleomycin increased ACE enzymatic activity and ACE mRNA, as monitored by hippuryl-L-histidyl-L-leucine assay and competitive quantitative reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Luciferase reporter constructs showed that upregulation of ACE transcription by bleomycin is mediated through element(s) in the 97-bp ACE promoter. Bleomycin activated p42/p44 mitogen-activated protein kinase (MAPK) and induced nuclear translocation and activation of the early growth response (Egr)-1 transcription factor, a factor previously shown to positively regulate ACE expression. The MAPK kinase1/2 (MEK1/2) inhibitor U0126 blocked MAPK and Egr-1 activation by bleomycin, suggesting that Egr-1 activation is MAPK dependent. These data provide the first evidence that bleomycin activates ACE gene expression through the MAPK pathway and Egr-1.

eng

IM

MEDLINE

1044-1549

Print

NLM

613-9

pubmed-meshheading:11713104-Animals, pubmed-meshheading:11713104-Antimetabolites, Antineoplastic, pubmed-meshheading:11713104-Base Sequence, pubmed-meshheading:11713104-Bleomycin, pubmed-meshheading:11713104-Butadienes, pubmed-meshheading:11713104-Cattle, pubmed-meshheading:11713104-Cells, Cultured, pubmed-meshheading:11713104-DNA-Binding Proteins, pubmed-meshheading:11713104-Enzyme Inhibitors, pubmed-meshheading:11713104-Gene Expression Regulation, Enzymologic, pubmed-meshheading:11713104-MAP Kinase Kinase 1, pubmed-meshheading:11713104-MAP Kinase Kinase 2, pubmed-meshheading:11713104-MAP Kinase Signaling System, pubmed-meshheading:11713104-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:11713104-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:11713104-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:11713104-Mitogen-Activated Protein Kinases, pubmed-meshheading:11713104-Molecular Sequence Data, pubmed-meshheading:11713104-Nitriles, pubmed-meshheading:11713104-Peptidyl-Dipeptidase A, pubmed-meshheading:11713104-Promoter Regions, Genetic, pubmed-meshheading:11713104-Protein-Serine-Threonine Kinases, pubmed-meshheading:11713104-Protein-Tyrosine Kinases, pubmed-meshheading:11713104-Pulmonary Artery, pubmed-meshheading:11713104-RNA, Messenger, pubmed-meshheading:11713104-Respiratory Mucosa, pubmed-meshheading:11713104-Transcription Factors

Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.