Brief Review

Aldosterone and Vascular Inflammation

Nancy J. Brown
https://doi.org/10.1161/HYPERTENSIONAHA.107.095489
Hypertension. 2008;51:161-167
Originally published January 23, 2008

Jump to

Oxidative stress and inflammation contribute to increased cardiovascular morbidity and mortality associated with activation of the renin-angiotensin (Ang)-aldosterone system (RAAS). Studies in cultured cells in vitro and in rodent models in vivo demonstrate that aldosterone and/or mineralocorticoid receptor (MR) activation cause oxidative stress and vascular inflammation. Translational studies in humans suggest that endogenous aldosterone increases inflammatory biomarkers through an MR-dependent pathway. Clinical studies indicate that the prevalence of hyperaldosteronism may be increased in resistant hypertension,1 that aldosterone concentrations “escape” to pretreatment levels during chronic treatment of congestive heart failure or hypertension with an Ang-converting enzyme (ACE) inhibitor or Ang receptor blocker,2–4 and that MR antagonism decreases mortality in congestive heart failure.5,6 This article reviews the current literature regarding mechanism(s) of aldosterone-induced vascular inflammation and its implications for the prevention of vascular injury in humans.

Role of Inflammation in Atherosclerosis and Vascular Remodeling

Oxidative stress and inflammation play central roles in the pathogenesis of atherosclerosis.7,8 Reactive oxygen species, including superoxide and hydrogen peroxide, modify vascular low-density lipoproteins to form oxidized low-density lipoproteins. Low-density lipoproteins stimulate endothelial cells to express leukocyte adhesion molecules, such as vascular cell adhesion molecule, leading to the recruitment of monocytes and T lymphocytes, which invade the intima. Monocyte-derived macrophages, rich in nicotinamide-adenine-dinucleotide phosphate (NADPH) oxidase, amplify the generation of reactant oxygen species. Macrophages take up oxidized low-density lipoproteins via scavenger receptors to become foam cells. T cells and macrophages within atherosclerotic lesions produce chemokines and cytokines resulting in the migration and proliferation of vascular smooth muscle cells (VSMCs) within the intima. VSMCs, in turn, promote extracellular matrix formation and secrete matrix metalloproteinases, contributing to the pathogenesis of plaque rupture.

Inflammation also triggers a cascade that leads to fibrosis and vascular remodeling.9 During inflammation, the recruitment of monocytes and macrophages promotes a proliferation of fibroblasts in the perivascular space. Cytokines like interleukin (IL)-6 stimulate the expression of profibrotic factors, such as transforming growth factor (TGF)-β and plasminogen activator inhibitor (PAI)-1. TGF-β stimulates cellular transformation to fibroblasts,10 increasing the synthesis of matrix proteins and integrins and decreasing production of matrix metalloproteinases.11 The net effect is increased collagen production and decreased extracellular matrix degradation, leading to fibrosis.

Activation of the RAAS Contributes to Oxidative Stress and Vascular Inflammation

It is now well-established that Ang II activates NADPH oxidases in VSMCs, monocytes, macrophages, and endothelial cells to produce reactive oxidant species.12–14 These reactive oxygen species stimulate the activation of proinflammatory transcription factors activator protein-1 and nuclear factor (NF) κB. NF-κB induces the production of adhesion molecules, chemokines such as monocyte chemoattractant protein (MCP)-1, and inflammatory cytokines. Recruitment of monocytes and macrophages may enhance the activity of the local vascular RAAS, because monocytes and macrophages express angiotensinogen, renin, ACE, and the Ang subtype 1 (AT1) receptor.15 Thus, upregulation of the RAAS during monocyte differentiation to macrophages may amplify monocyte migration into the vascular wall.

Recent data from Guzik et al16 further support a role for vascular inflammation in the pathogenesis of Ang II–induced hypertension. Fourteen-day infusion of Ang II caused T-lymphocyte infiltration in the aortic adventitia and periaortic fat, vascular superoxide production, endothelial dysfunction, and hypertension in mice. Mice lacking T and B lymphocytes were protected against the development of oxidative stress, endothelial dysfunction, and hypertension, whereas adoptive transfer of T cells, but not B cells, restored the hypertensive response to Ang II. Hypertension was also prevented by the tumor necrosis factor-α antagonist etanercept.

Aldosterone Induces Inflammation in Rodent Models

Seminal studies in rat models in the 1990s demonstrated that MR activation causes perivascular and interstitial fibrosis in the heart, aortic fibrosis and remodeling, and renal injury.17–23 Work, completed over the last decade, established a critical role for inflammation in initiating fibrosis and remodeling in response to exogenous aldosterone or MR activation. For example, Fiebeler et al24 investigated the contribution of MR activation to proinflammatory and profibrotic mediators in the heart of rats doubly transgenic for the human renin and angiotensinogen genes. MR antagonism prevented vascular injury and cardiac fibrosis, activation of activator protein-1 and NF-κB, and upregulation of basic fibroblast growth factor in the hearts of rats doubly transgenic for the human renin and angiotensinogen genes. Rocha et al25 demonstrated that 4-week treatment with aldosterone and salt caused extensive inflammatory arterial lesions with perivascular macrophages in the heart. MR blockade decreased this inflammatory response. Aldosterone/salt also increased the expression of intercellular adhesion molecule, cyclooxygenase-2, osteopontin, and MCP-1, effects that were decreased by MR blockade.

MR antagonism decreases aortic inflammation, fibrosis, and hypertrophy in hypertensive rats.21,23,26 MR antagonism decreases oxidative stress and inflammation, as measured by tumor necrosis factor-α and MCP-1 expression, in apolipoprotein E–deficient mice fed a high-cholesterol diet, a model of atherosclerosis.27 Furthermore, like Ang II, the mineralocorticoid deoxycorticosterone acetate causes aortic superoxide production and hypertension through a T-cell–dependent mechanism.16

Treatment of rats with aldosterone and salt causes perivascular leukocyte infiltration and increased expression of osteopontin, MCP-1, IL-6, and IL-1β in the kidney, as well, through an MR-dependent mechanism.28 Treatment with deoxycorticosterone acetate and salt also causes leukocyte infiltration and increased expression of NADPH oxidase and hemooxygenase-1 subunits, cyclooxygenase-2, osteopontin, and TGF-β in the kidney; interestingly, Lam et al29 have reported that MR antagonism reduces expression of cyclooxygenase-2 and NADPH oxidase subunits but not leukocyte infiltration or osteopontin expression in this model. In contrast, Fiebeler et al30 reported that aldosterone synthase inhibition or AT1 receptor antagonism decreased monocyte, macrophage, and CD24 T-cell infiltration in the kidneys of rats doubly transgenic for the human renin and angiotensinogen genes. MR activation also contributes to inflammatory changes in diabetic nephropathy; thus, treatment of type 1 or type 2 diabetic rats with an MR antagonist decreases macrophage infiltration and expression of MCP-1 and migration inhibitory factor in the kidney.31,32

Increased cytokines and MR activation also increase the expression of PAI-1. PAI-1, a member of the serpin superfamily and the major physiological inhibitor of tissue-type plasminogen activator and urokinase plasminogen activator in vivo, decreases both direct and indirect effects of plasmin on extracellular matrix degradation but also decreases plasmin-mediated activation of TGF-β and cell migration.33,34 Thus, whereas PAI-1 contributes to vascular remodeling and renal injury during excess Ang II or aldosterone,35,36 increased PAI-1 expression protects against cardiac fibrosis, likely by decreasing urokinase-dependent macrophage infiltration.11,37,38

Microarray Studies Confirm the Proinflammatory Effects of Aldosterone

Whole animal studies of the proinflammatory effects of aldosterone may be confounded by systemic effects on sodium and potassium homeostasis. Genetic expression studies in cultured VSMCs and cardiomyocytes confirm the proinflammatory and profibrotic effects of aldosterone. Exposure of human coronary artery smooth muscle cells to aldosterone upregulates the lymphocyte chemoattractant factor IL-16 and cytotoxic T-lymphocyte–associated protein 4, as well as type I and type III collagens.39 Fejes-Tóth and Náray-Fejes-Tóth40 demonstrated that exposure of MR-expressing cardiomyocytes to a physiological concentration (1 nM) of aldosterone in vitro induces rapid increases in the expression of genes involved in inflammation and fibrosis, including orosomucoid-1, PAI-1, and tenascin-X.

Aldosterone Stimulates Inflammation Through the Generation of Reactive Oxygen Species

Like Ang II, aldosterone activates NADPH oxidases in rat VSMCs.41 Similarly, aldosterone increases expression of the NADPH oxidase subunit p22phox in human monocytes42 and promotes apoptosis in human renal proximal tubular cells via the MR-dependent generation of reactive oxygen species.43 In human endothelial vein cells, aldosterone inhibits NO synthase by inducing the oxidation of its cofactor 5,6,7,8-tetrahydrobiopterin, as well as by activating protein phosphatase 2A.44 Aldosterone treatment also produces oxidative stress and endothelial dysfunction in mice by decreasing the vascular expression of glucose-6-phosphate dehydrogenase, which reduces oxidized nicotinamide-adenine dinucleotide phosphate to NADPH.45

Systemic administration of aldosterone increases oxidative stress in the heart,46 vasculature, and kidney47–49 and increases macrophage NADPH oxidase (Figure).50 MR activation contributes to Ang II–mediated activation of NADPH oxidase in the heart and aorta.51–53 Exogenous aldosterone stimulates aortic expression of p22phox and NOX2 (gp91phox) through an MR-dependent mechanism and of p47phox mRNA through both AT1 receptor and MR-dependent mechanisms.48 Increased oxidative stress activates the redox sensitive NF-κB, triggering inflammation. Hence, aldosterone-stimulated activation of NF-κB in the heart is prevented in NOX2-deficient mice.52 Likewise, the administration of antioxidant drugs, such as the superoxide dismutase mimetic Tempol,47,48,54 the NADPH oxidase inhibitor apocynin,55 or N-acetylcysteine46 decreases inflammation and injury in aldosterone-treated rodents. Increased expression of endothelin may also contribute to oxidative stress and increased expression of adhesion molecules during mineralocorticoid excess.56–58

Figure1

Figure. Cartoon of mechanism(s) of aldosterone-induced vascular fibrosis: aldosterone, acting at the MR, affects the transcription of proinflammatory genes. Aldosterone also causes rapid, transcription-independent effects. Aldosterone activates NADPH oxidases to produce reactive oxygen species (O2−). Ang II increases MR-dependent transcription in VSMCs via its AT1 receptor. Aldosterone and Ang II phosphorylate ERK1/2 through genomic and nongenomic pathways. Nongenomic pathways involve transactivation of the EGFR. Increased oxidative stress and activation of ERK result in the expression of proinflammatory transcription factors, adhesion factors, such as intercellular adhesion molecule (ICAM)-1, and chemokines like MCP-1. Leukocytes secrete inflammatory cytokines (IL-6), which, in turn, promote expression of profibrotic factors, such as TGF-β and PAI-1.

High salt intake enables the effects of aldosterone on oxidative stress, inflammation, and fibrosis in whole animal models through a potassium-independent mechanism.59 Ahokas et al60 have noted that, during high salt intake, activation of the MR causes Ca2+ loading and a fall in cytosolic free-ionized Mg2+ in monocytes and cardiomyocytes through a mechanism involving Na+-Mg2+ and Na+-Ca2+ exchangers. Intracellular Ca2+ loading, in turn, causes oxidative stress. Mihailidou and Funder61 suggest that changes in intracellular redox potential result in activation of cortisol (corticosterone)-MR complexes in nonepithelial tissues, such as the heart. Upregulation of local tissue RAAS (in contradistinction to the circulating RAAS) during high salt intake may also contribute to oxidant stress.62 Interestingly, in the presence of aldosterone, small increases in plasma sodium decrease NO release and increase the stiffness of endothelial cells in culture.63

Complex Interactions Among Ang II, Aldosterone, and Their Receptors Contribute to Inflammation

Although aldosterone induces vascular inflammation through direct effects at the MR, aldosterone also enhances the proinflammatory effects of Ang II. For example, aldosterone increases vascular ACE expression and local Ang II concentrations.48,64,65 Aldosterone upregulates vascular AT1 receptor expression.66,67 Aldosterone potentiates Ang II–induced signaling via activation of mitogen-activated protein kinases in VSMCs.68 Conversely, Ang II activates MR responsive elements through an AT1-dependent mechanism in human coronary artery smooth muscle cells.39 Activation of the MR by Ang II does not involve aldosterone synthesis, because aldosterone synthase inhibition does not prevent the effect. In vivo, treatment with an AT1 receptor antagonist can prevent aldosterone-induced perivascular inflammation and fibrosis in the heart.69

Glucocorticoids also activate the MR, possibly explaining the observation that MR antagonism decreases inflammation even under conditions when endogenous aldosterone concentrations are not elevated. The MR binds cortisol and aldosterone with equal affinity. In epithelial tissues, the enzyme 11β-hydroxysteroid 2 converts cortisol (or, in rodents, corticosterone) to its inactive 11-ketometabolite, such that MRs are activated primarily by aldosterone.70 Cardiomyocytes do not express 11β-hydroxysteroid 2, and, therefore, cortisol, present in higher concentrations, acts as the primary MR ligand.71 In contrast, the vasculature expresses 11β-hydroxysteroid 2 such that aldosterone activates the MR. The observation that cardiomyocyte-specific overexpression of 11β-hydroxysteroid 2 in mice causes cardiac hypertrophy and fibrosis, which is reversed by eplerenone, has led investigators to hypothesize that cortisol (corticosterone) exerts a tonic inhibitory effect at the MR in the heart71; as noted earlier, Mihailidou and Funder61 proposed that changes in intracellular redox potential activate cortisol MR during high salt intake.

Aldosterone Can Exert Proinflammatory Effects via MR-Dependent and -Independent Pathways

Activation of the MR by aldosterone results in its dissociation from molecular chaperones, translocation into the nucleus, and binding to hormone response elements in the regulatory region of target gene promoters to enhance expression. Aldosterone can also exert rapid, nongenomic effects, however, particularly in VSMCs, and many of these effects are not blocked by the MR antagonist spironolactone but may be blocked by its open-ring, water-soluble metabolite, canrenoate, or by eplerenone.72,73 Studies in fibroblasts derived from MR-deficient mice and in MR-transfected cells suggest that the MR contributes to the rapid effects of aldosterone on the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun NH2-terminal kinase pathway but not to rapid effects on calcium.74,75 In rabbit heart, aldosterone increases Na+/K+/2Cl− cotransporter activity and decreases Na+/K+ pump activity through a nongenomic effect on protein kinase C-ε,76 which stimulates NF-κB activation via mitogen-activated protein kinases.77 Although MR antagonists prevent the inflammatory effects of aldosterone in most rodent models, studies in cultured VSMCs suggest the possibility of an MR-independent proinflammatory effect of aldosterone.

Specifically, in VSMCs, phosphorylation or activation of p38, mitogen-activated protein kinases, and ERK1/2 results in the production of cytokines and chemokines.78 Aldosterone rapidly activates ERK1/2 in VSMCs.79 Aldosterone also enhances both rapid and delayed activation of ERK1/2 by Ang II. Treatment with spironolactone or with inhibitors of transcription and protein synthesis prevent the late effect of aldosterone and Ang II, suggesting that this effect occurs through an MR-dependent, genomic pathway. In contrast, spironolactone does not block rapid phosphorylation of ERK1/2 by aldosterone. The early phase involves the transactivation of the epidermal growth factor receptor (EGFR), whereas the late phase involves increased expression of the fibrotic and proliferative small and monomeric GTP-binding protein Ki-ras2A and mitogen-activated protein kinase.79 Mazak et al68 similarly reported that spironolactone reduced Ang II–stimulated ERK1/2 activation and EGFR phosphorylation at 10 minutes but not at 2 minutes. As noted earlier, lack of blockade by spironolactone need not exclude an MR-dependent mechanism. In human aortic smooth muscle cells, aldosterone induces EGFR expression via an interaction between the ligand-bound MR and regions 316 to 163 and 163 to 1 bp of the EGFR promoter.80

Evidence for a Proinflammatory Effect of Aldosterone in Humans

In rodent models of hyperaldosteronism, vascular inflammation can be assessed directly by quantification of monocyte and macrophage infiltration of the vascular wall. New imaging techniques, such as18fluorodeoxyglucose positron-emission tomography, allow for the assessment of local vascular inflammation in humans.81 To date, however, studies of the proinflammatory effects of aldosterone or MR activation in humans have relied on the measurement of circulating biomarkers of inflammation. These include the chemokines tumor necrosis factor-α and MCP-1, inflammatory cytokines, C-reactive protein, and PAI-1. Although beyond the scope of the present review, elevations of many of these biomarkers have been associated with the development of hypertension and with endothelial dysfunction, cardiovascular events, and renal injury in hypertensive patients.82

Irita et al83 compared concentrations of IL-6, tumor necrosis factor-α, C-reactive protein, and osteopontin in the sera or plasma of patients with primary hyperaldosteronism and in age-matched patients with essential hypertension; osteopontin concentrations were higher in primary hyperaldosteronism. Increased osteopontin expression contributes to atherosclerosis and vascular remodeling,84 and primary hyperaldosteronism is associated with endothelial dysfunction,85 cardiac fibrosis,86 and increased risk of myocardial infarction, stroke, and atrial fibrillation.87

Twelve-hour infusion of aldosterone increases circulating IL-6 and IL-12 concentrations in normal volunteers to levels comparable to those associated with endothelial dysfunction after vaccination.88,89 Intravenous infusion of Ang II also increases IL-6 concentrations. This effect is blocked by spironolactone, suggesting that Ang II induces inflammation via an MR-dependent mechanism. Although these studies used exogenous Ang II or aldosterone to achieve supraphysiological concentrations, activation of the endogenous RAAS by low salt intake or diuretic use is associated with increased circulating concentrations of IL-689 and PAI-1.90

Studies using spironolactone or eplerenone further elucidate the effect of endogenous aldosterone or MR activation on oxidative stress and inflammatory biomarkers. The results of these studies differ, depending on the biomarker studied. Takebayashi et al91 compared the effect of spironolactone and the calcium channel blocker amlodipine on oxidative stress, as measured by urinary excretion of F2-isoprostanes, and on urinary excretion of MCP-1. Although both drugs decreased blood pressure, only spironolactone decreased urinary F2-isoprostanes and MCP-1.

Our group has studied the effect of spironolactone on circulating PAI-1 concentrations.92–94 PAI-1 represents both an acute-phase reactant and a potent inhibitor of fibrinolysis. Aldosterone and PAI-1 have been reported to predict the development of the metabolic syndrome in the Framingham Offspring Study.95 Spironolactone decreases PAI-1 concentrations in hypertensive subjects taking hydrochlorothiazide, whereas the MR-independent potassium-sparing diuretic triamterene does not.94 MR and AT1 antagonists synergistically decrease PAI-1 concentrations in diuretic-treated normotensive subjects.93 Two other groups have reported that spironolactone decreases PAI-1 concentrations.96,97 In contrast, MR antagonism does not seem to decrease concentrations of C-reactive protein.96,98

Perspectives

Studies in vitro and in vivo in rodent models indicate an important role for aldosterone and MR activation in the induction of oxidative stress and inflammation leading to endothelial dysfunction and vascular remodeling during activation of the RAAS. Oxidative stress and inflammation result from complex interactive effects of aldosterone on the actions of Ang II at its AT1 receptor, as well as from activation of the MR by Ang II and other ligands. Moreover, in the vasculature, the activation of inflammatory signaling pathways may involve both genomic and nongenomic mechanisms.

Studies indicating that exogenous aldosterone and Ang II increase, whereas MR blockade decreases; inflammatory or fibrotic biomarkers in humans confirm the relevance of these findings. MR blockade reduces mortality in patients with congestive heart failure or left ventricular dysfunction after myocardial infarction, and in the Randomized Aldactone Evaluation Study the effect of spironolactone on a biomarker of fibrosis, procollagen type III amino-terminal peptide, predicted the reduction in mortality.99 Given recent data in the mouse indicating that vascular inflammation contributes to the development of hypertension during activation of the RAAS, as well as data from epidemiologic studies indicating that circulating biomarkers of inflammation predict the development of hypertension, furthermore, it is possible that the proinflammatory effects of aldosterone or MR activation could also contribute to the development of hypertension in humans.

Acknowledgments

Sources of Funding

This work was supported by National Institutes of Health grants HL060906, HL077389, and HL079184.

Disclosures

N.J.B. serves as advisor or consultant for Novartis and Via Pharmaceuticals.

  • Received October 1, 2007.
  • Revision received October 21, 2007.
  • Accepted November 30, 2007.

References

  1. ↵
    Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002; 40: 892–896.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Struthers AD. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J. 1995; 16: 103–106.
    OpenUrlAbstract
  3. ↵
    McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ, Probstfield J, Tsuyuki RT, White M, Rouleau J, Latini R, Maggioni A, Young J, Pogue J. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation. 1999; 100: 1056–1064.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res. 2001; 29: 13–21.
    OpenUrlPubMed
  5. ↵
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341: 709–717.
    OpenUrlCrossRefPubMed
  6. ↵
    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.
    OpenUrlCrossRefPubMed
  7. ↵
    Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.
    OpenUrlCrossRefPubMed
  8. ↵
    Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508–519.
    OpenUrlCrossRefPubMed
  9. ↵
    Weber KT. From inflammation to fibrosis: a stiff stretch of highway. Hypertension. 2004; 43: 716–719.
    OpenUrlFREE Full Text
  10. ↵
    Okada H, Danoff TM, Kalluri R, Neilson EG. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 1997; 273: F563–F574.
    OpenUrlPubMed
  11. ↵
    Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM, Davidson JM, Sheppard D, Fogo AB. Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(−/−) mice. Am J Pathol. 2003; 163: 1261–1273.
    OpenUrlCrossRefPubMed
  12. ↵
    Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74: 1141–1148.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Zhang H, Schmeisser A, Garlichs CD, Plotze K, Damme U, Mugge A, Daniel WG. Angiotensin II-induced superoxide anion generation in human vascular endothelial cells: role of membrane-bound NADH-/NADPH-oxidases. Cardiovasc Res. 1999; 44: 215–222.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Hazan-Halevy I, Levy T, Wolak T, Lubarsky I, Levy R, Paran E. Stimulation of NADPH oxidase by angiotensin II in human neutrophils is mediated by ERK, p38 MAP-kinase and cytosolic phospholipase A2. J Hypertens. 2005; 23: 1183–1190.
    OpenUrlCrossRefPubMed
  15. ↵
    Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Takiuchi S, Moriguchi K, Fennessy PA, Higaki J, Ogihara T. Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages. J Hypertens. 1999; 17: 537–545.
    OpenUrlCrossRefPubMed
  16. ↵
    Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007; 204: 2449–2460.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med. 1992; 120: 893–901.
    OpenUrlPubMed
  18. ↵
    Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol. 1993; 25: 563–575.
    OpenUrlCrossRefPubMed
  19. ↵
    Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest. 1994; 93: 2578–2583.
    OpenUrlCrossRefPubMed
  20. ↵
    Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996; 98: 1063–1068.
    OpenUrlCrossRefPubMed
  21. ↵
    Benetos A, Lacolley P, Safar ME. Prevention of aortic fibrosis by spironolactone in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 1997; 17: 1152–1156.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Lacolley P, Safar ME, Lucet B, Ledudal K, Labat C, Benetos A. Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. J Am Coll Cardiol. 2001; 37: 662–667.
    OpenUrlCrossRefPubMed
  23. ↵
    Lacolley P, Labat C, Pujol A, Delcayre C, Benetos A, Safar M. Increased carotid wall elastic modulus and fibronectin in aldosterone-salt-treated rats: effects of eplerenone. Circulation. 2002; 106: 2848–2853.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Fiebeler A, Schmidt F, Muller DN, Park JK, Dechend R, Bieringer M, Shagdarsuren E, Breu V, Haller H, Luft FC. Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. Hypertension. 2001; 37: 787–793.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Rocha R, Rudolph AE, Frierdich GE, Nachowiak DA, Kekec BK, Blomme EA, McMahon EG, Delyani JA. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002; 283: H1802–H1810.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Neves MF, Amiri F, Virdis A, Diep QN, Schiffrin EL. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol. 2005; 83: 999–1006.
    OpenUrlCrossRefPubMed
  27. ↵
    Suzuki J, Iwai M, Mogi M, Oshita A, Yoshii T, Higaki J, Horiuchi M. Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation. Arterioscler Thromb Vasc Biol. 2006; 26: 917–921.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Blasi ER, Rocha R, Rudolph AE, Blomme EA, Polly ML, McMahon EG. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 2003; 63: 1791–1800.
    OpenUrlCrossRefPubMed
  29. ↵
    Lam EY, Funder JW, Nikolic-Paterson DJ, Fuller PJ, Young MJ. Mineralocorticoid receptor blockade but not steroid withdrawal reverses renal fibrosis in deoxycorticosterone/salt rats. Endocrinology. 2006; 147: 3623–3629.
    OpenUrlCrossRefPubMed
  30. ↵
    Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al Saadi N, Dechend R, Wellner M, Meiners S, Maser-Gluth C, Jeng AY, Webb RL, Luft FC, Muller DN. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation. 2005; 111: 3087–3094.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, Han KH, Kim HK, Kang YS, Han JY, Kim YS, Cha DR. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006; 17: 1362–1372.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, Kikuchi T, Lapointe N, Pojoga L, Williams GH, Ricchiuti V, Adler GK. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology. 2006; 147: 5363–5373.
    OpenUrlCrossRefPubMed
  33. ↵
    Gils A, Declerck PJ. Plasminogen activator inhibitor-1. Curr Med Chem. 2004; 11: 2323–2334.
    OpenUrlCrossRefPubMed
  34. ↵
    Stefansson S, Lawrence DA. Old dogs and new tricks: proteases, inhibitors, and cell migration. Sci STKE. 2003; 2003: e24.
    OpenUrl
  35. ↵
    Weisberg AD, Albornoz F, Griffin JP, Crandall DL, Elokdah H, Fogo AB, Vaughan DE, Brown NJ. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol. 2005; 25: 365–371.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Ma J, Weisberg A, Griffin JP, Vaughan DE, Fogo AB, Brown NJ. Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 2006; 69: 1064–1072.
    OpenUrlCrossRefPubMed
  37. ↵
    Oestreicher EM, Martinez-Vasquez D, Stone JR, Jonasson L, Roubsanthisuk W, Mukasa K, Adler GK. Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury. Circulation. 2003; 108: 2517–2523.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Moriwaki H, Stempien-Otero A, Kremen M, Cozen AE, Dichek DA. Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice. Circ Res. 2004; 95: 637–644.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Jaffe IZ, Mendelsohn ME. Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res. 2005; 96: 643–650.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Fejes-Tóth G, Náray-Fejes-Tóth A. Early aldosterone-regulated genes in cardiomyocytes: clues to cardiac remodeling? Endocrinology. 2007; 148: 1502–1510.
    OpenUrlCrossRefPubMed
  41. ↵
    Callera GE, Touyz RM, Tostes RC, Yogi A, He Y, Malkinson S, Schiffrin EL. Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension. 2005; 45: 773–779.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    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.
    OpenUrlCrossRefPubMed
  43. ↵
    Patni H, Mathew JT, Luan L, Franki N, Chander PN, Singhal PC. Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress. Am J Physiol Renal Physiol. 2007; 293: F1065–F1071.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    Nagata D, Takahashi M, Sawai K, Tagami T, Usui T, Shimatsu A, Hirata Y, Naruse M. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension. 2006; 48: 165–171.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Leopold JA, Dam A, Maron BA, Scribner AW, Liao R, Handy DE, Stanton RC, Pitt B, Loscalzo J. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med. 2007; 13: 189–197.
    OpenUrlCrossRefPubMed
  46. ↵
    Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol. 2002; 161: 1773–1781.
    OpenUrlCrossRefPubMed
  47. ↵
    Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T. Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. Hypertension. 2007; 49: 355–364.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Hirono Y, Yoshimoto T, Suzuki N, Sugiyama T, Sakurada M, Takai S, Kobayashi N, Shichiri M, Hirata Y. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: the possible role of local renin-angiotensin system. Endocrinology. 2007; 148: 1688–1696.
    OpenUrlCrossRefPubMed
  49. ↵
    Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, Kondo S, Kiyomoto H, Shokoji T, Kimura S, Kohno M, Abe Y. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension. 2004; 43: 841–848.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Keidar S, Kaplan M, Pavlotzky E, Coleman R, Hayek T, Hamoud S, Aviram M. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation. 2004; 109: 2213–2220.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension. 2002; 40: 504–510.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    Johar S, Cave AC, Narayanapanicker A, Grieve DJ, Shah AM. Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J. 2006; 20: 1546–1548.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Stas S, Whaley-Connell A, Habibi J, Appesh L, Hayden MR, Karuparthi PR, Qazi M, Morris EM, Cooper SA, Link CD, Stump C, Hay M, Ferrario C, Sowers JR. Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. Endocrinology. 2007; 148: 3773–3780.
    OpenUrlCrossRefPubMed
  54. ↵
    Iglarz M, Touyz RM, Viel EC, Amiri F, Schiffrin EL. Involvement of oxidative stress in the profibrotic action of aldosterone: interaction with the renin-angiotension system. Am J Hypertens. 2004; 17: 597–603.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Park YM, Park MY, Suh YL, Park JB. NAD(P)H oxidase inhibitor prevents blood pressure elevation and cardiovascular hypertrophy in aldosterone-infused rats. Biochem Biophys Res Commun. 2004; 313: 812–817.
    OpenUrlCrossRefPubMed
  56. ↵
    Li L, Fink GD, Watts SW, Northcott CA, Galligan JJ, Pagano PJ, Chen AF. Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension. Circulation. 2003; 107: 1053–1058.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Callera GE, Montezano AC, Touyz RM, Zorn TM, Carvalho MH, Fortes ZB, Nigro D, Schiffrin EL, Tostes RC. ETA receptor mediates altered leukocyte-endothelial cell interaction and adhesion molecules expression in DOCA-salt rats. Hypertension. 2004; 43: 872–879.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Wong S, Brennan FE, Young MJ, Fuller PJ, Cole TJ. A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology. 2007; 148: 1511–1517.
    OpenUrlCrossRefPubMed
  59. ↵
    Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, Williams GH, Adler GK. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertension. 2002; 39: 614–618.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Ahokas RA, Sun Y, Bhattacharya SK, Gerling IC, Weber KT. Aldosteronism and a proinflammatory vascular phenotype: role of Mg2+, Ca2+, and H2O2 in peripheral blood mononuclear cells. Circulation. 2005; 111: 51–57.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Mihailidou AS, Funder JW. Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system. Steroids. 2005; 70: 347–351.
    OpenUrlCrossRefPubMed
  62. ↵
    Bayorh MA, Ganafa AA, Emmett N, Socci RR, Eatman D, Fridie IL. Alterations in aldosterone and angiotensin II levels in salt-induced hypertension. Clin Exp Hypertens. 2005; 27: 355–367.
    OpenUrlCrossRefPubMed
  63. ↵
    Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A. 2007; 104: 16281–16286.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Harada E, Yoshimura M, Yasue H, Nakagawa O, Nakagawa M, Harada M, Mizuno Y, Nakayama M, Shimasaki Y, Ito T, Nakamura S, Kuwahara K, Saito Y, Nakao K, Ogawa H. Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation. 2001; 104: 137–139.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Sugiyama T, Yoshimoto T, Tsuchiya K, Gochou N, Hirono Y, Tateno T, Fukai N, Shichiri M, Hirata Y. Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. Endocrinology. 2005; 146: 3900–3906.
    OpenUrlCrossRefPubMed
  66. ↵
    Schiffrin EL, Franks DJ, Gutkowska J. Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol. 1985; 63: 1522–1527.
    OpenUrlPubMed
  67. ↵
    Ullian ME, Schelling JR, Linas SL. Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses. Hypertension. 1992; 20: 67–73.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    Mazak I, Fiebeler A, Muller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation. 2004; 109: 2792–2800.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    Robert V, Heymes C, Silvestre JS, Sabri A, Swynghedauw B, Delcayre C. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension. 1999; 33: 981–986.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science. 1988; 242: 583–585.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Qin W, Rudolph AE, Bond BR, Rocha R, Blomme EA, Goellner JJ, Funder JW, McMahon EG. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res. 2003; 93: 69–76.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Michea L, Delpiano AM, Hitschfeld C, Lobos L, Lavandero S, Marusic ET. Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. Endocrinology. 2005; 146: 973–980.
    OpenUrlCrossRefPubMed
  73. ↵
    Boldyreff B, Wehling M. Aldosterone: refreshing a slow hormone by swift action. News Physiol Sci. 2004; 19: 97–100.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    Haseroth K, Gerdes D, Berger S, Feuring M, Gunther A, Herbst C, Christ M, Wehling M. Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout mice. Biochem Biophys Res Commun. 1999; 266: 257–261.
    OpenUrlCrossRefPubMed
  75. ↵
    Grossmann C, Benesic A, Krug AW, Freudinger R, Mildenberger S, Gassner B, Gekle M. Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol Endocrinol. 2005; 19: 1697–1710.
    OpenUrlCrossRefPubMed
  76. ↵
    Mihailidou AS, Mardini M, Funder JW. Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology. 2004; 145: 773–780.
    OpenUrlCrossRefPubMed
  77. ↵
    Li RC, Ping P, Zhang J, Wead WB, Cao X, Gao J, Zheng Y, Huang S, Han J, Bolli R. PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. Am J Physiol Heart Circ Physiol. 2000; 279: H1679–H1689.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    Mukundan L, Milhorn DM, Matta B, Suttles J. CD40-mediated activation of vascular smooth muscle cell chemokine production through a Src-initiated, MAPK-dependent pathway. Cell Signal. 2004; 16: 375–384.
    OpenUrlCrossRefPubMed
  79. ↵
    Min LJ, Mogi M, Li JM, Iwanami J, Iwai M, Horiuchi M. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res. 2005; 97: 434–442.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Grossmann C, Krug AW, Freudinger R, Mildenberger S, Voelker K, Gekle M. Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter. Am J Physiol Endocrinol Metab. 2007; 292: E1790–E1800.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    Tahara N, Kai H, Yamagishi S, Mizoguchi M, Nakaura H, Ishibashi M, Kaida H, Baba K, Hayabuchi N, Imaizumi T. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J Am Coll Cardiol. 2007; 49: 1533–1539.
    OpenUrlCrossRefPubMed
  82. ↵
    Pickering TG. Stress, inflammation, and hypertension. J Clin Hypertens (Greenwich). 2007; 9: 567–571.
    OpenUrlCrossRefPubMed
  83. ↵
    Irita J, Okura T, Manabe S, Kurata M, Miyoshi K, Watanabe S, Fukuoka T, Higaki J. Plasma osteopontin levels are higher in patients with primary aldosteronism than in patients with essential hypertension. Am J Hypertens. 2006; 19: 293–297.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007; 27: 2302–2309.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension. 1993; 21: 929–933.
    OpenUrlPubMed
  86. ↵
    Rossi GP, Di B, V, Ganzaroli C, Sacchetto A, Cesari M, Bertini A, Giorgi D, Scognamiglio R, Mariani M, Pessina AC. Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension. 2002; 40: 23–27.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005; 45: 1243–1248.
    OpenUrlCrossRefPubMed
  88. ↵
    Clapp BR, Hirschfield GM, Storry C, Gallimore JR, Stidwill RP, Singer M, Deanfield JE, MacAllister RJ, Pepys MB, Vallance P, Hingorani AD. Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation. 2005; 111: 1530–1536.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Luther JM, Gainer JV, Murphey LJ, Yu C, Vaughan DE, Morrow JD, Brown NJ. Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension. 2006; 48: 1050–1057.
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin angiotensin system on plasma PAI-1 in humans. Hypertension. 1998; 32: 965–971.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Takebayashi K, Matsumoto S, Aso Y, Inukai T. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab. 2006; 91: 2214–2217.
    OpenUrlCrossRefPubMed
  92. ↵
    Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ. Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab. 2002; 87: 448–452.
    OpenUrlCrossRefPubMed
  93. ↵
    Sawathiparnich P, Murphey LJ, Kumar S, Vaughan DE, Brown NJ. Effect of combined AT1 receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin Endocrinol Metab. 2003; 88: 3867–3873.
    OpenUrlCrossRefPubMed
  94. ↵
    Ma J, Albornoz F, Yu C, Byrne DW, Vaughan DE, Brown NJ. Differing effects of mineralocorticoid receptor-dependent and -independent potassium-sparing diuretics on fibrinolytic balance. Hypertension. 2005; 46: 313–320.
    OpenUrlAbstract/FREE Full Text
  95. ↵
    Ingelsson E, Pencina MJ, Tofler GH, Benjamin EJ, Lanier KJ, Jacques PF, Fox CS, Meigs JB, Levy D, Larson MG, Selhub J, D’Agostino RB Sr, Wang TJ, Vasan RS. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study. Circulation. 2007; 116: 984–992.
    OpenUrlAbstract/FREE Full Text
  96. ↵
    Matsumoto S, Takebayashi K, Aso Y. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism. 2006; 55: 1645–1652.
    OpenUrlCrossRefPubMed
  97. ↵
    Kasifoglu T, Yalcin AU. The effects of thiazide and thiazide-potassium sparing diuretics on fibrinolytic system parameters. Anadolu Kardiyol Derg. 2006; 6: 143–147.
    OpenUrlPubMed
  98. ↵
    Godfrey V, Farquharson CA, Macdonald JE, Yee KM, Struthers AD. Effect of spironolactone on C-reactive protein levels in patients with heart disease. Int J Cardiol. 2007; 117: 282–284.
    OpenUrlCrossRefPubMed
  99. ↵
    Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000; 102: 2700–2706.
    OpenUrlAbstract/FREE Full Text
View Abstract

This Issue

Jump to

Article Tools

Share this Article

  • Email
  • Aldosterone and Vascular Inflammation
    Nancy J. Brown
    Hypertension. 2008;51:161-167, originally published January 23, 2008
    https://doi.org/10.1161/HYPERTENSIONAHA.107.095489
    Permalink:
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects