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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 613-619

Bleomycin Upregulates Gene Expression of Angiotensin-Converting Enzyme via Mitogen-Activated Protein Kinase and Early Growth Response 1 Transcription Factor

Regina M. Day, Yongzhen Yang, Yuichiro J. Suzuki, Joanne Stevens, Renuka Pathi, Amy Perlmutter, Barry L. Fanburg, and Joseph J. Lanzillo

New England Medical Center, Tupper Research Institute, Pulmonary and Critical Care Division; and Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts

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 µg/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.

Abbreviations: angiotensin converting enzyme, ACE; angiotensin II, Ang II; bovine pulmonary artery endothelial cells, BPAEC; complementary DNA, cDNA; deoxynucleoside triphosphate, dNTP; dithiothreitol, DTT; ethylenediaminetetraacetic acid, EDTA; early growth response 1, Egr-1; electrophoretic mobility shift assay, EMSA; hepatocyte growth factor, HGF; human umbilical vein endothelial cells, HUVEC; nitro-L-arginine methyl ester, L-NAME; mitogen-activated protein kinase, MAPK; MAPK kinase1/2, MEK1/2; Moloney murine leukemia virus reverse transcriptase, MMLV-RT; phosphate-buffered saline, PBS; polymerase chain reaction, PCR; phorbol 12-myristate acetate, PMA; platelet-derived growth factor, PDGF; phenylmethylsulfonyl fluoride, PMSF; reactive oxygen species, ROS; transforming growth factor-beta 1, TGF-beta 1.




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