Glucocorticoids induce angiotensin-converting enzyme expression in vascular smooth muscle.
Angiotensin-converting enzyme (ACE) activity plays a central role in vessel growth and remodeling as shown by the fact that ACE inhibitors reduce neointimal proliferation after rat carotid injury. To investigate the mechanisms that regulate smooth muscle cell ACE expression, we studied the effects of steroids on ACE activity and mRNA in cultured rat aortic smooth muscle cells. ACE activity was present at low levels independent of growth state. In response to the glucocorticoid dexamethasone (100 nmol/L for 72 hours), ACE activity (hydrolysis of [3H]benzoyl-Phe-Ala-Pro) increased 10.1 +/- 3.1-fold. The increase in activity occurred within 12 hours and peaked after 72 hours of treatment. The increase in ACE activity was specific for glucocorticoids and paralleled their potency (dexamethasone > hydrocortisone = prednisolone). Dexamethasone increased the steady-state level of ACE mRNA in a concentration-dependent manner (21.4 +/- 0.4-fold at 100 nmol/L for 72 hours). Dexamethasone stimulation of ACE expression appeared to be due to both increased transcription and stabilization of ACE enzyme mRNA. This was suggested by the finding that dexamethasone stimulated nuclear run-on expression of ACE mRNA by only threefold, in contrast to the 21-fold increase in steady-state mRNA. These findings establish that ACE is a dynamically regulated enzyme in rat aortic smooth muscle cells. In addition, the present findings suggest an important role for stress steroids in the vascular response to injury in vivo.
Fishel
R S
RS
Department of Medicine, Emory University, Atlanta, Ga.
Eisenberg
S
S
Shai
S Y
SY
Redden
R A
RA
Bernstein
K E
KE
Berk
B C
BC
D000818:Animals; D002417:Cattle / Q000196:embryology; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D005938:Glucocorticoids; D012333:RNA, Messenger; D003907:Dexamethasone; D007703:Peptidyl-Dipeptidase A