title: Inhibition of neutrophil-dependent cytotoxicity for human endothelial cells by ACE inhibitors.
abstract: Angiotensin-converting enzyme inhibitors (ACEi) have immunomodulating properties and have been suggested to protect against endothelial injury, for example myocardial infarction and reperfusion injury. We tested whether two ACEi (captopril and enalapril), differing in a thiol group, protected human umbilical vein endothelial cells (HUVEC) from cytotoxicity induced by polymorphonuclear neutrophils (PMN) in vitro, when cells were activated by tumour necrosis factor-α (TNFα) or the arachidonate derivative lipoxin-A4 (LXA4 ), using separate cytotoxicity pathways. When (51) Cr labelled HUVEC were treated with captopril (0-500 μm) or enalapril (0-100 μm) for 2 h and then activated by TNFα (100 ng/ml) for 24 h, a significant, dose-dependent reduction of (51) Cr release was observed. Similarly, captopril reduced (51) Cr release when LXA4 (0.1 μm) was used to stimulate PMN for 4 h. Among previously defined mechanisms of significance for the cytotoxic reaction, expression of ICAM-1, but not intracellular Ca(2+) changes in PMN or PMN adherence to HUVEC, were reduced by ACEi treatment. Moreover, both ACEi inhibited HUVEC surface expression of TNFα receptor I (but not II). Thus, these ACEi, particularly captopril, interfere with PMN-induced cytotoxicity for endothelial cells by modulating pro-inflammatory surface receptors, which is a novel effect that might be explored for further therapeutic approaches.
authors.affiliation: Department of Medicine, Stockholm Soder Hospital, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Andersson
authors.forename: J
authors.initials: J
authors.lastname: Bratt
authors.forename: M
authors.initials: M
authors.lastname: Heimbürger
authors.forename: T
authors.initials: T
authors.lastname: Cederholm
authors.forename: J
authors.initials: J
authors.lastname: Palmblad
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004656:Enalapril / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D056747:Immunomodulation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D044045:Lipoxins / Q000494:pharmacology; D009203:Myocardial Infarction / Q000517:prevention & control; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007155:Immunologic Factors; D044045:Lipoxins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D018799:Intercellular Adhesion Molecule-1; D004656:Enalapril; D002216:Captopril