Signaling via the angiotensin-converting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells.
Angiotensin-converting enzyme (ACE) inhibitors elicit outside-in signaling via ACE in endothelial cells. This involves the CK2-mediated phosphorylation of ACE on Ser1270 and the activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway, resulting in an enhanced endothelial ACE expression. Because cyclooxygenase-2 (COX-2) expression is reported to be increased in subjects treated with ACE inhibitors, we determined the role of ACE signaling in this phenomenon and the transcription factors involved. In lungs from mice treated with the ACE inhibitor ramipril for 5 days, COX-2 expression was increased. A similar (1.5- to 2-fold) increase in COX-2 protein was detected in primary cultures of human endothelial cells treated with ramiprilat. In an endothelial cell line stably expressing human somatic ACE, ramiprilat increased COX-2 promoter activity, an effect not observed in ACE-deficient cells or cells expressing a nonphosphorylatable ACE mutant (S1270A). The ramiprilat-induced, ACE-dependent increase in COX-2 expression and promoter activity (both 1.5- to 2-fold greater than control) was prevented by the inhibition of JNK. Ramiprilat significantly enhanced the DNA binding activity of activator protein-1 in cells expressing ACE but not S1270A ACE. Activator protein-1 decoy oligonucleotides prevented the ACE inhibitor-induced increase in COX-2 promoter activity and protein expression. As a consequence of the ramiprilat-induced increase in COX-2 expression, prostacyclin and prostaglandin E2, but not thromboxane A2, production was increased and was inhibited by the COX-2 inhibitor celecoxib. These results indicate that ACE signaling may underlie the increase in COX-2 and prostacyclin levels in patients treated with ACE inhibitors.
Kohlstedt
Karin
K
Vascular Signaling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Busse
Rudi
R
Fleming
Ingrid
I
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D019943:Amino Acid Substitution; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta; D001667:Binding, Competitive; D000068579:Celecoxib; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D044062:Prostaglandins I / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000494:pharmacology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D034421:Sus scrofa; D013928:Thromboxane A2 / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000873:Anthracenes; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D044062:Prostaglandins I; D011720:Pyrazoles; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C052549:ramiprilat; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; D000068579:Celecoxib; D015232:Dinoprostone; D017257:Ramipril