AJP - Cell Physiology, Vol 263, Issue 4 C743-C749, Copyright © 1992 by American Physiological Society
Converting-enzyme inhibitors increase converting-enzyme mRNA and activity in endothelial cells
S. J. King and S. Oparil
Department of Cell Biology, University of Alabama, Birmingham 35294.
Exposure to angiotensin-converting-enzyme (ACE) inhibitors has been
associated with increased ACE activity in vivo and in vitro. In the current
study, we examined the effects of the active site-directed ACE inhibitors
lisinopril and captopril on ACE gene expression and activity in cultured
porcine pulmonary artery endothelial cells. Exposure of endothelial cells
to both lisinopril and captopril was associated with increased ACE mRNA
levels and concomitant increases in ACE activity. These effects were both
concentration and time dependent. ACE mRNA levels began to increase within
30 min of ACE inhibitor exposure and showed an early peak at 2 h and a
higher, delayed peak at 48 h. ACE activity peaked at 24 h. Both ACE mRNA
levels and activity were highest during incubation with 100 microM
inhibitor. Nuclear runoff assays indicated that 48 h of exposure to 100
microM of either captopril or lisinopril increased ACE gene transcription
approximately threefold relative to a tubulin control, a level comparable
to the increases in ACE mRNA levels and activity observed during ACE
inhibitor exposure. These findings support the hypothesis that ACE gene
expression endothelial cells is stimulated by active site-directed ACE
inhibitors in vitro. This provides a molecular mechanism for the
observation that plasma and tissue ACE activity in vivo is increased during
chronic exposure to ACE inhibitors.
