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2005, Hypertension
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2 pages
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Takai et al have recently demonstrated a possible role of aldosterone in endothelial dysfunction since eplerenone strengthens the endothelium-dependent relaxation and prevents atherosclerosis in monkey fed with a high cholesterol diet but with normal aldosterone plasma levels. 1 However, the title of the editorial commentary related to this article, "Eplerenone antagonizes atherosclerosis, but what is the agonist?," 2 is emblematic of the difficulty to relate eplerenone and normal aldosterone concentration to inflammation and atherosclerosis. Aldosterone has been involved in the genesis of inflammation. This process is preceded by peripheral blood mononuclear leukocytes (MNL) invasion, and it is still uncertain whether MNL are activated before tissue invasion or they are attracted in the site of inflammation by local factors. We have demonstrated that peripheral MNL of healthy subjects possess mineralocorticoid receptors (MR) 3 that are sensitive to aldosterone in terms of oxidative stress induction. 4 In particular, coincubation of MNL with canrenone, a MR antagonist, abolished the MNL expression of 2 oxidative stress-related proteins, p22 phox and plasminogen activator inhibitor-1, which was already evident at baseline. This result is consistent with an effect of endogenous concentration of aldosterone and with the possibility that MNL, once attracted in the site of inflammation, would drive MR directly within the vascular wall, allowing endogenous aldosterone to act as proinflammatory factor. In addition, our study was performed at the physiological concentration of sodium, therefore ruling out high sodium as a requisite for aldosterone to induce oxidative stress. The increased prooxidant effect of high aldosterone concentration was blocked by coincubation of MNL with canrenone. 4 These results support the findings of Takai et al 1 as their study was performed in animals fed a normal sodium diet, and the effect of eplerenone was evident even in the presence of a normal aldosterone concentration. Further support to the antiatherosclerotic effect of eplerenone comes from the demonstration that eplerenone induced reduction of oxidative stress and arteriosclerosis progression in apolipoprotein E-deficient mice through reduction of macrophage oxidative capacity and lipid peroxides. 5 This, as for the study of Takai et al, 1 also underlines the role of increased availability of cholesterol for the induction of inflammation. Based on the information coming from our study 4 and on the report of literature 1,5 we suggest that a possible link between aldosterone, even at physiological concentration, inflammation, and atherosclerosis reported by Takai et al 1 could derive by the inflammatory process induced by the increased cholesterol concentration at the level of the arterial wall, which attracts MNL with the MR available for binding of aldosterone that, even in normal concentration, may act as a proinflammatory factor and that is blocked by the binding of eplerenone on MNL MR. The confirmation of these hypotheses could also provide the clinical rationale for the usefulness of aldosterone receptor blockers as antiinflammatory/antiremodeling agents in hypercholesterolemia independently from aldosterone concentration and blood pressure level.
2010
Background-The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E-deficient (E 0 ) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect. Methods and Results-Aldosterone (0.2 to 6 g · mouse Ϫ1 · d Ϫ1 ) was administered to E 0 mice alone or in combination with eplerenone (200 mg · kg Ϫ1 · d Ϫ1 ), ramipril (5 mg · kg Ϫ1 · d Ϫ1 ), or losartan (25 mg · kg Ϫ1 · d Ϫ1 ). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation, because increased translocation of its cytosolic component p47 phox to the macrophage plasma membrane was observed. THP-1 macrophages incubated in vitro with aldosterone (10 mol/L) exhibited a higher capacity to release superoxide ions by 110% and increased ability to oxidize LDL by 74% compared with control cells. Aldosterone administration enhanced mouse peritoneal macrophage ACE activity and mRNA expression by 2.3-fold and 2.4-fold, respectively. Only cotreatment of eplerenone with ramipril or losartan completely blocked the oxidative effects of aldosterone. Conclusions-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.
Circulation, 2004
Background— The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E–deficient (E 0 ) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect. Methods and Results— Aldosterone (0.2 to 6 μg · mouse −1 · d −1 ) was administered to E 0 mice alone or in combination with eplerenone (200 mg · kg −1 · d −1 ), ramipril (5 mg · kg −1 · d −1 ), or losartan (25 mg · kg −1 · d −1 ). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably...
Circulation, 2002
Background-Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis. Methods and Results-New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O 2 ⅐Ϫ ) generation. SARA normalized O 2 ⅐Ϫ generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31Ϯ0.04 and 0.27Ϯ0.02 in HL versus 0.16Ϯ0.05 and 0.07Ϯ0.02 in HL-SARA, respectively; PϽ0.01 by ANOVA). This was associated with improvements in peak relaxations to the endothelial-dependent agonist acetylcholine (82Ϯ6% in HL-SARA versus 61Ϯ4 in HL; PϽ0.01 by ANOVA; ED 50 6.8ϫ10 Ϫ8 mol/L in HL-SARA and 1.2ϫ10 Ϫ7 mol/L in HL; PϭNS) to near-normal levels. Vessels from the HL group demonstrated hyperreactivity to angiotensin II that could not be corrected with SARA. Plasma aldosterone levels by radioimmunoassay demonstrated a 4-to 5-fold increase in response to SARA but no differences with lipid feeding. Real-time reverse transcriptase-polymerase chain reaction studies revealed expression of MR in the aorta of HL rabbits and those of controls.
Trends in Endocrinology and Metabolism, 2001
Heart disease and stroke are the first and third leading causes of death, respectively, in the USA 1 . Although the percentage of hypertensive patients receiving treatment has increased, and blood pressure is now better controlled, the incidence of end-stage renal disease and the prevalence of heart failure continue to increase 2 . This suggests that blood pressure reduction alone is not sufficient to prevent end-organ damage and that the additional control of local and/or hormonal factors might be essential. Abnormal activation of the renin-angiotensin-aldosterone system (RAAS) correlates directly with the incidence and extent of endorgan damage 3,4 . Moreover, numerous clinical and experimental studies have demonstrated that blockade of the RAAS with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists provides significant cardiovascular protection 5-9 . Therefore, it has been proposed that overactivation of the RAAS represents a cardiovascular risk factor 10 .
Diabetes & Metabolism, 2004
Cells in the cortical collecting duct of distal nephron have been considered for a long time as the unique cellular targets of aldosterone. However, it is now clear that other cell types in non-epithelial tissues are also potential targets for aldosterone. The functions that this hormone controls in non-epithelial tissues are still a matter of debate. Clinical and experimental studies have established that aldosterone plays a major role in the pathophysiology of cardiovascular and renal diseases. The aldosterone receptor antagonists spironolactone and eplerenone have demonstrated specific effects not related to their hypotensive properties in hypertension or cardiac diseases. It appears that a key action of these molecules is related to prevention or treatment of end-organ damage. The latter fact, and the recognition of aldosterone escape on long-term treatment of heart failure, diabetic nephropathy and some forms of hypertension with ACE inhibitors, justify the clinical use of aldosterone receptor antagonists provided that kaliemia is controlled. Experimental studies have allowed to draw a still incomplete but comprehensive scheme of aldosterone cardiovascular actions in pathological conditions. When elevated, aldosterone has deleterious effects in blood vessels, in the heart and in kidney, which are secondary to the induction of inflammatory and oxidative processes and necrosis, that induce the increased synthesis of extracellular matrix proteins.
In Analysis, 2023
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