Human neutrophil peptides upregulate expression of COX-2 and endothelin-1 by inducing oxidative stress.
Polymorphonuclear leukocytes (PMNs) play an important role during inflammation in cardiovascular diseases. Human neutrophil peptides (HNPs) are released from PMN granules upon activation and are conventionally involved in microbial killing. Recent studies suggested that HNPs may be involved in the pathogenesis of vascular abnormality by modulating inflammatory responses and vascular tone. Since HNPs directly interact with endothelium upon release from PMNs in the circulation, we tested the hypothesis that the stimulation with HNPs of endothelial cells modulates the expression of vasoactive by-products through altering cyclooxygenase (COX) activity. When human umbilical vein endothelial cells were stimulated with purified HNPs, we observed a time- and dose-dependent increase in the expression of COX-2, whereas COX-1 levels remained unchanged. Despite an increased expression of COX-2 at the protein level, HNPs did not significantly enhance the COX-2 activity, thus the production of the prostaglandin PGI2. HNPs significantly induced the release of endothelin-1 (ET-1) as well as the formation of nitrotyrosine. The HNP-induced COX-2 and ET-1 production was attenuated by the treatment with the oxygen free radical scavenger N-acetyl-L-cysteine and the inhibitors of p38 MAPK and NF-kappaB, respectively. The angiontensin II pathway did not seem to be involved in the HNP-induced upregulation of COX-2 and ET-1 since the use of the angiotensin-converting enzyme inhibitor enalapril had no effect in this context. In conclusion, HNP may play an important role in the pathogenesis of inflammatory cardiovascular diseases by activating endothelial cells to produce vasoactive by-products as a result of oxidative stress.
Syeda
Farisa
F
The Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Canada.
Tullis
Elizabeth
E
Slutsky
Arthur S
AS
Zhang
Haibo
H
D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D016166:Free Radical Scavengers; D016328:NF-kappa B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; C002744:3-nitrotyrosine; D014443:Tyrosine; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases