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(Hypertension. 1995;26:230-235.)
© 1995 American Heart Association, Inc.

Articles

Regulation and Differential Expression of Neutral Endopeptidase 24.11 in Human Endothelial Cells

Presented in part at the scientific sessions of the American Heart Association, 1992 and 1993, and published in abstract form (Circulation. 1992;86[suppl I]:I-275; Circulation. 1993;88[suppl I]:I-315).

Kristof Graf; Petra Koehne; Michael Gräfe; Minzhong Zhang; Wolfgang Auch-Schwelk; Eckart Fleck

From the Department of Internal Medicine/Cardiology and Angiology, Free University and German Heart Institute Berlin (K.G., M.G., W.A.-S., E.F.), and the Department of Clinical Immunology, Free University Berlin, Universitätsklinikum Rudolf Virchow (P.K., M.Z.) (Germany).

Abstract Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360±14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099±73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 µmol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 µmol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 µmol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 µmol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158±26% and 150±22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 µmol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.

Key Words: endothelium • enzymes • phorbols • protein kinases • thrombin

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