Abstract-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 (PϽ0.005) 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 (PϽ0.01) 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), cardiac ACE2 activity significantly (PϽ0.05) 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 mol/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.
Intravenous Ig therapy (IVIg) is reported to be a useful regimen in treating autoimmune diseases. In this study, we asked whether IVIg (in vitro) could increase the expression of TGF-β, IL-10, and the transcription factor FoxP3 in T regulatory (Treg) cells, and the idea that IVIg could enhance suppressive properties of these cells. CD4+ T cells from 12 healthy individuals were cultured in the presence or absence of IVIg vs human control IgG during 16, 24, and 36 h. Using FACS analysis and gating on CD4+CD25high Treg cells, we assessed the expression of intracellular TGF-β, IL-10, and FoxP3. In addition, the production of TNF-α by stimulated CD4+ T cells alone or in culture with CD25+ by itself or together with IVIg was also assessed. The presence of IVIg with Treg cells in culture significantly increased the intracellular expression of TGF-β (17.7 ± 8.5% vs 29.8 ± 13%; p = 0.02), IL-10 (20.7 ± 4.7% vs 34.2 ± 5.2%; p = 0.008) and FoxP3 (20.8 ± 5.2% vs 33.7 ± 5.9%; p = 0.0006) when compared with cells cultured alone or with control human IgG. The suppressive effect of CD4+CD25+ T cells presented as the decrease of TNF-α production by stimulated CD4+CD25− (effector T cells) was further increased by adding IVIg to cell culture. We hereby demonstrate an additional mechanism by which IVIg could maintain self-tolerance and decrease immune-mediated inflammation.
Oxidative stress is involved in the pathogenesis of atherosclerosis, and angiotensin II (AT-II) induces oxidative stress and enhances atherogenesis. Aldosterone, which has an important role in the pathology of heart failure, has recently been implicated as a mediator of AT-II biologic activities. In this study, we analyzed whether administration of the selective aldosterone blocker eplerenone to atherosclerotic apolipoprotein E-deficient (E0) mice would affect their oxidative status and atherogenesis. Apolipoprotein E-deficient mice were administered chow containing eplerenone (200 mg/kg/day) for 3 months. Blood pressure, serum and macrophage oxidative status, and aortic atherosclerotic lesion area were evaluated in mice treated with eplerenone compared with untreated mice. Eplerenone administration significantly decreased systolic and diastolic blood pressure by 12% and 11%, respectively, compared with untreated mice. Serum susceptibility to lipid peroxidation decreased by as much as 26%, and serum paraoxonase activity increased by 28% in eplerenone-treated mice compared with untreated mice. Peritoneal macrophages from eplerenone-treated mice contained reduced levels of lipid peroxides, and their macrophage oxidation of low-density lipoprotein (LDL) and superoxide ion release were significantly reduced (by 17% and 43%, respectively), compared to untreated mice. Daily injections of AT-II (0.1 mL, 10(-)7M) during the final 3 weeks of the study in eplerenone-treated mice substantially attenuated the eplerenone-mediated reduction in macrophage superoxide release and LDL oxidation. Finally, the atherosclerotic lesion area in aortas of eplerenone-treated mice was significantly reduced (by 35%) versus untreated mice, and this effect was reversed by AT-II. Administration of the selective aldosterone blocker eplerenone significantly reduced oxidative stress and atherosclerosis progression in E0 mice. These data suggest that aldosterone could have a significant pro-oxidative role in the pathogenesis of atherosclerosis.
Aldosterone administration to E(0) mice increased macrophage oxidative stress and atherosclerotic lesion development. Blocking of the mineralocorticoid receptor and inhibition of tissue ACE and/or the angiotensin receptor-1 reduced aldosterone deleterious pro-oxidative and proatherogenic effects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.