| Circ Res. 2005 Sep 22; [Epub ahead of print] |
|
| Mineralocorticoid Receptor Blocker Increases Angiotensin-Converting
Enzyme 2 Activity in Congestive Heart Failure Patients |
|
| Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S,
Hayek T, Karry R, Abassi Z |
|
| Lipid Research Laboratory, Department of Vascular Surgery and Transplantation,
and the Department of Physiology and Biophysics, The Bruce Rappaport
Faculty of Medicine, Technion; and The Rappaport Family Institute for
Research in the Medical Sciences and Rambam Medical Center, Haifa,
Israel |
|
Aldosterone plays an important role in the pathophysiology of congestive
heart failure (CHF), and spironolactone improves cardiovascular function
and survival rates in patients with CHF. We hypothesized that the mineralocorticoid
receptor blockade (MRB) exerted its beneficial effects by reducing
oxidative stress and changing the balance between the counter-acting
enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived
macrophages were obtained from 10 patients with CHF before and after
1 month of treatment with spironolactone (25 mg/d). Spironolactone
therapy significantly (P<0.005) reduced oxidative stress, as expressed
by reduced lipid peroxide content, superoxide ion release, and low-density
lipoprotein oxidation by 28%, 53%, and 70%, respectively. Although
spironolactone significantly (P<0.01) reduced macrophage ACE activity
by 47% and mRNA expression by 53%, ACE2 activity and mRNA expression
increased by 300% and 654%, respectively. In mice treated for 2 weeks
with eplerenone (200 mg . kg(-1) . d(-1)), cardiac ACE2 activity significantly
(P<0.05) increased by 2-fold and was paralleled by increased ACE2
activity in macrophages. The mechanism of aldosterone antagonist action
was studied in mouse peritoneal macrophages (MPMs) in vitro. Although
ACE activity and mRNA were significantly increased by 250 nmol/L aldosterone,
ACE2 was significantly reduced. Cotreatment with eplerenone (2 micromol/L)
attenuated these effects. In MPM obtained from p47 knockout mice, where
NADPH oxidase is inactive, as well as in control MPMs treated with
NADPH oxidase inhibitor, aldosterone did not increase ACE or decrease
ACE2. MRB reduced oxidative stress, decreased ACE activity, and increased
ACE2 activity, suggesting a protective role for MRB by possibly increasing
generation of angiotensin (1-7) and decreasing formation of angiotensin
II. These effects are mediated, at least in part, by NADPH oxidase.
|
