Lipopolysaccharides decrease angiotensin converting enzyme activity expressed by cultured human endothelial cells.
Angiotensin converting enzyme (ACE) is present on endothelial cells and plays a role in regulating blood pressure in vivo by converting angiotensin I to angiotensin II and metabolizing bradykinin. Since ACE activity is decreased in vivo in sepsis, the ability of lipopolysaccharide (LPS) to suppress endothelial cell ACE activity was tested by culturing human umbilical vein endothelial cells (HUVEC) for 0-72 hr with or without LPS and then measuring ACE activity. ACE activity in intact HUVEC monolayers incubated with LPS (10 micrograms/ml) decreased markedly with time and was inhibited by 33%, 71%, and 76% after 24 hr, 48 hr, and 72 hr, respectively, when compared with control, untreated cells. The inhibitory effect of LPS was partially reversible upon removal of the LPS and further incubation in the absence of LPS. The LPS-induced decrease in ACE activity was dependent on the concentrations of LPS (IC50 = 15 ng/ml at 24 hr) and was detectable at LPS concentrations as low as 1 ng/ml. That LPS decreased the Vmax of ACE in the absence of cytotoxicity and without a change in Km suggests that LPS decreased the amount of ACE present on the HUVEC cell membrane. While some LPS serotypes (Escherichia coli 0111:B4 and 055:B5, S. minnesota) were more potent inhibitors of ACE activity than others (E. coli 026:B6 and S. marcescens), all LPS serotypes tested were inhibitory. These finding suggest that LPS decreases endothelial ACE activity in septic patients; in turn, this decrease in ACE activity may decrease angiotensin II production and bradykinin catabolism and thus play a role in the pathogenesis of septic shock.
Watanabe
K
K
Department of Medicine, Cornell University Medical College, New York, New York 10021.
Lam
G
G
Keresztes
R S
RS
Jaffe
E A
EA
D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology*; D004926:Escherichia coli; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012475:Salmonella; D012706:Serratia marcescens; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D001427:Bacterial Toxins; D008070:Lipopolysaccharides; D003907:Dexamethasone; D007703:Peptidyl-Dipeptidase A; D013755:Tetradecanoylphorbol Acetate