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(Circulation Research. 1996;79:512-523.)
© 1996 American Heart Association, Inc.

Articles

Monocyte- and Cytokine-Induced Downregulation of Angiotensin-Converting Enzyme in Cultured Human and Porcine Endothelial Cells

Andreas Papapetropoulos, Alexander Antonov, Renu Virmani, Frank D. Kolodgie, David H. Munn, Nandor Marczin, James W. Ryan, Ross G. Gerrity, John D. Catravas

the Vascular Biology Center (A.P., N.M., J.W.R., J.D.C.), the Department of Pharmacology and Toxicology (A.P., N.M., J.W.R., J.D.C.), the Department of Pathology (A.A., R.G.G.), the Department of Pediatrics (D.H.M.), and the Department of Anesthesiology (J.W.R.), Medical College of Georgia, Augusta, and the Armed Forces Institute of Pathology (R.V., F.D.K.), Washington, DC.

Correspondence to Dr John D. Catravas, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500.

We investigated the effects of monocytes on endothelial cell (EC) ectoenzyme activity. Coculture of human aortic ECs with human monocytes (2x10⁵ monocytes per 2-cm² well) led to a decrease in EC angiotensin-converting enzyme (ACE) activity (64.5±3.5% of control) but not aminopeptidase N, aminopeptidase P, and 5'-nucleotidase activities. Similar results were obtained using human umbilical vein EC–human monocyte and porcine aortic EC–porcine monocyte cocultures. The decrease in ACE activity was monocyte concentration and coculture time dependent, reaching a maximum of 65% decrease in activity at 120 hours. Monocyte-mediated reduction in ACE activity did not require cell to cell contact, since exposure of ECs to conditioned medium from cocultures (CCCM) or from monocyte cultures (MCM) produced a decrease in ACE activity similar to that observed in EC-monocyte cocultures. Exogenously added tumor necrosis factor (TNF)- and interleukin (IL)-1, two known secretory products of monocytes, simulated the effects of monocytes on ACE activity. Western blot analysis revealed a decrease in the amount of ACE protein in TNF-–treated and CCCM-treated ECs compared with control ECs. Both TNF- and IL-1 were present in CCCM and MCM but not EC-conditioned medium. Incubation of the cocultures with a mixture of neutralizing antibodies against TNF- and IL-1 totally abolished the monocyte-induced decrease in ACE activity. In conclusion, monocytes decrease ACE activity in cultured ECs through the release of cytokines such as TNF- and IL-1.

Key Words: angiotensin-converting enzyme • 5'-nucleotidase • surface peptidase • tumor necrosis factor- • interleukin-1

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