GLUCOCORTICOIDS INDUCE ANGIOTENSIN-CONVERTING ENZYME EXPRESSION IN VASCULAR SMOOTH-MUSCLE

Angiotensin-converting enzyme (ACE) activity plays a central role in v essel growth and remodeling as shown by the fact that ACE inhibitors r educe neointimal proliferation after rat carotid injury. To investigat e the mechanisms that regulate smooth muscle cell ACE expression, we s tudied the effects of steroids on ACE activity and mRNA in cultured ra t aortic smooth muscle cells. ACE activity was present at low levels i ndependent of growth state. In response to the glucocorticoid dexameth asone (100 nmol/L for 72 hours), ACE activity (hydrolysis of [H-3]benz oyl Phe-Ala-Pro) increased 10.1+/-3.1-fold. The increase in activity o ccurred within 12 hours and peaked after 72 hours of treatment. The in crease in ACE activity was specific for glucocorticoids and paralleled their potency (dexamethasone>hydrocortisone=prednisolone). Dexamethas one increased the steady-state level of ACE mRNA in a concentration-de pendent manner (21.4+/-0.4-fold at 100 nmol/L for 72 hours). Dexametha sone stimulation of ACE expression appeared to be due to both increase d transcription and stabilization of ACE enzyme mRNA. This was suggest ed by the finding that dexamethasone stimulated nuclear run-on express ion of ACE mRNA by only threefold, in contrast to the 21-fold increase in steady-state mRNA. These findings establish that ACE is a dynamica lly regulated enzyme in rat aortic smooth muscle cells. In addition, t he present findings suggest an important role for stress steroids in t he vascular response to injury in vivo.