Estrogen regulation of angiotensin-converting enzyme mRNA

Estrogen replacement therapy is cardioprotective in postmenopausal women; h owever, the precise molecular mechanisms for this modulation are not fully elucidated. We previously showed that chronic estrogen replacement therapy reduced angiotensin-converting enzyme (ACE) activity in tissue extracts and serum with an associated reduction in plasma angiotensin II, A reverse tra nscriptase-polymerase chain reaction assay was developed to determine wheth er estrogen treatment regulates tissue ACE mRNA concentration. Total RNA wa s isolated from kidney cortex, kidney medulla, lung, and aorta of ovariecto mized Sprague-Dawley rats after 21 days of chronic 17 beta-estradiol replac ement therapy (5 mg pellet per rat SC) or placebo. A marked decrease in den sitometric intensity ratios of amplified ACE cDNA to elongation factor-1 al pha control cDNA was observed in all tissues from placebo-treated rats comp ared with the estradiol-treated rats (renal cortex: 0.29+/-0.04 versus 0.14 +/-0.02; renal medulla: 0.37+/-0.04 versus 0.24+/-0.03; lung: 4.49+/-0.37 v ersus 2.49+/-0.59; and aorta: 0.41+/-0.04 versus 0.29+/-0.02; all P<0.05). A comparable reduction in ACE activity was detected in tissue extracts from kidney cortex, kidney medulla, and lung of hormone-treated animals. Incuba tion of purified rat lung ACE with 1 or 10 mu mol/L 17 beta-estradiol had n o effect on enzyme activity. These results suggest that estrogen treatment regulates tissue ACE activity by reducing ACE mRNA concentrations. Thus, th e beneficial cardiovascular effects of estrogen may be mediated in part by downregulation of ACE with a consequent reduction in the circulating levels of the vasoconstrictor angiotensin II, a decrease in the metabolism of the vasodilator bradykinin, and an increase in the production of the vasorelax ant angiotensin-(1-7).