Academia.eduAcademia.edu

Mononuclear Leukocyte Mineralocorticoid Receptors * Response

2005, Hypertension

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.

Letter to the Editor Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed, double-spaced) in length and may be subject to editing or abridgment. Decio Armanini Cristina Fiore Departments of Medical and Surgical Sciences—Endocrinology University of Padua Padua, Italy Mononuclear Leukocyte Mineralocorticoid Receptors A Possible Link Between Aldosterone and Atherosclerosis Downloaded from http://ahajournals.org by on June 6, 2020 To the Editor: 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, p22phox 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 al1 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 study4 and on the report of literature1,5 we suggest that a possible link between aldosterone, even at physiological concentration, inflammation, and atherosclerosis reported by Takai et al1 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. Lorenzo A Calò Department of Clinical and Experimental Medicine University of Padua Padua, Italy 1. Takai S, Jin D, Muramatsu M, Kirimura K, Sakonjo H, Miyazaki M. Eplerenone inhibits atherosclerosis in nohuman primates. Hypertension. 2005;46:1135–1139. 2. Strawn WB. Eplerenone antagonizes atherosclerosis, but what is the agonist? Hypertension. 2005;46: 46:1093–1094. 3. Armanini D, Strasser T, Weber PC. Characterization of aldosterone binding sites in circulating human mononuclear leukocytes. Am J Physiol. 1985;248:E388 –E390. 4. Calo LA, Zaghetto F, Pagnin E, Davis PA, De Mozzi P, Sartorato P, Martire G, Fiore C, Armanini D. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab. 2004;89:1973–1976. 5. Keidar S, Hayek T, Kaplan M, Pavlotzky E, Hamoud S, Coleman R, Aviram M. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and arteriosclerosis in apolipoprotein E-deficent mice. J Cardiovasc Pharmacol. 2003;41:955–963. Response Activation of mineralocorticoid receptors (MR) in peripheral blood mononuclear leukocytes (MNL) increased oxidative stress, which might play an important role in the development and progression of atherosclerosis.1 In the editorial commentary,2 Strawn suggested the following 4 possibilities for MR activation in arteriosclerotic lesions: (1) increased MR numbers; (2) increased aldosterone synthesis; (3) MR activation caused by elevated angiotensin II production; and (4) MR activation by oxidative stress. All of these mechanisms are likely involved in the progression of arteriosclerosis. However, what first activates MR in the hyperlipidemic model? In our model, elevated low-density lipoprotein (LDL)-cholesterol and decreased high-density lipoprotein (HDL)-cholesterol were observed. The imbalance between LDL-cholesterol and HDL-cholesterol during the early stage might increase the oxidative stress.3 MR have been suggested to be directly stimulated by oxidative stress, independently of aldosterone stimulation.4 Therefore, increased oxidative stress caused by an imbalance between LDL-cholesterol and HDL-cholesterol might initially activate MR in MNL and macrophages. Keidar et al5 demonstrated that eplerenone reduced not only macrophage oxidative stress but also macrophage angiotensin-converting enzyme expression. This suggests the possibility that MR stimulation increases angiotensin II production, which in turn stimulates angiotensin II receptor, thus increasing oxidative stress. In the hyperlipidemic model, MR blockers suppress oxidative stress and angiotensin II production, whereas angiotensin II receptor blockers suppress oxidative stress and aldosterone synthesis.5 Such an aggravating cycle involving oxidative stress, MR stimulation, and angiotensin II receptor stimulation could play an important role in the development of arteriosclerosis in the hyperlipidemic model. Therefore, therapy combining the drugs that alleviate oxidative stress, suppress angiotensin II action, and e4 Letter to the Editor inhibit MR is expected to potently suppress arteriosclerosis by strongly inhibiting the aggravating cycle. Shinji Takai Mizuo Miyazaki Department of Pharmacology Osaka Medical College Osaka, Japan 1. Calo LA, Zaghetto F, Pagnin E, Davis PA, De Mozzi P, Sartorato P, Martire G, Fiore C, Armanini D. Effect of aldosterone and glycyrrhetinic 2. 3. 4. 5. e5 acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J Clin Endocrinol Metab. 2004;89:1973–1976. Strawn WB. Eplerenone antagonizes atherosclerosis, but what is the agonist? Hypertension. 2005;46:1093–1094. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95:764 –772. Funder JW. Aldosterone, mineralocorticoid receptors and vascular inflammation. Mol Cell Endocrinol. 2004;217:263–269. Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, Karry R, Abassi Z. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. 2005;97:946 –953. Downloaded from http://ahajournals.org by on June 6, 2020