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From the Department of Medicine,* Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, Tennessee; and the Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana
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Abstract |
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B activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-
mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91phox and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-B activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.
The pathophysiological basis for the induction of oxidative stress in these settings has been related to an activation of NADPH oxidase, a major determinant of vascular tissue redox state, transduced by circulating neurohormones that include angiotensin (Ang) II28 and catecholamines.29 Herein, we hypothesized that aldosterone (ALDO), another member of the renin-angiotensin-aldosterone system, likewise contributes to the induction of oxidative stress and the proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury in the rodent heart in response to ALDO/salt administration and that would be sustained with chronic treatment. We and others have shown that this model rapidly suppresses plasma renin activity and circulating angiotensin II while raising plasma levels of this steroid molecule to those found in congestive heart failure or with adrenal adenoma.30 We compared ALDO-treated rodents to those co-treated with an ALDO receptor antagonist, spironolactone (Spi), or with an antioxidant, either pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), and to untreated/unoperated, age-matched controls.
We monitored the temporal and spatial association between molecular and cellular events associated with this phenotype. This specifically included: immunohistochemical detection of 1) NADPH oxidase, a major source of reactive oxygen species within the vasculature, via expression of its membrane-bound flavoprotein subunit (gp91phox); 2) expression of 3-nitrotyrosine, a stable protein moiety formed by the interaction of superoxide with nitric oxide and resultant peroxynitrite reaction with tyrosine residues, which is indicative of nitrosative stress; and 3) activation of redox-sensitive transcription factor nuclear factor-B (NF-B) and specifically its RelA subunit. By in situ hybridization we localized mRNA expression of genes regulated by NF-B. These included intercellular adhesion molecule (ICAM)-1; monocyte chemoattractant protein (MCP)-1; and a proinflammatory cytokine, tumor necrosis factor (TNF)-. Cellular responses were examined by immunohistochemical detection of macrophages, T lymphocytes, and cell growth by BrdU labeling. Finally, the histochemical detection of fibrosis was monitored by picrosirius red labeling and collagen volume fraction at vascular and nonvascular sites of cardiac injury was determined by videodensitometry.
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Materials and Methods |
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Eight-week-old male Sprague-Dawley rats (Harlan, Indianapolis, IN) were used in this study. Five animal groups were studied (n = 8 in each group): 1) untreated and unoperated rats served as controls; 2) uninephrectomized rats on 1% NaCl/0.4% KCl diet received ALDO (0.75 µg/hour) by implanted minipump for 3, 4, or 5 weeks; 3) uninephrectomized rats on the same salt diet and dose of ALDO also received an ALDO receptor antagonist, Spi (200 mg/kg/day),31
given by gavage for 4 weeks; 4) uninephrectomized rats on the same salt diet received ALDO plus an antioxidant, PDTC (200 mg/kg s.c. daily),32
also considered an inhibitor of NF-B, for 4 weeks; and 5) uninephrectomized rats on the same salt diet received ALDO plus an antioxidant, NAC (200 mg/kg i.p. daily) for 4 weeks. Animals were sacrificed at weeks 3, 4, and 5. The dose of ALDO selected raises its plasma levels to those seen in humans with congestive heart failure.33
Rats received BrdU (25 mg/rat, i.p.) for 3 days before sacrifice. Hearts were removed, rinsed in cold saline solution, and frozen in isopentane with dry ice for in situ hybridization, immunohistochemistry, and histochemistry. The study was approved by this Institution’s Animal Care and Use Committee.
NADPH Oxidase and 3-Nitrotyrosine Expression and NF-B Activation
Coronal cryostat sections (6 µm) were prepared, air-dried, fixed in 10% buffered formalin for 5 minutes, and washed in phosphate-buffered saline (PBS) for 10 minutes. Sections were then incubated with primary antibody against gp91phox at a dilution of 1:100;34 3-nitrotyrosine at a dilution of 1:100 (Upstate Biotech, Lake Placid, NY); or anti-RelA (Chemicon, Temecula, CA) at a dilution of 1:100 in PBS containing 1% bovine serum albumin for 60 minutes. Sections were then washed in PBS for 10 minutes and incubated with IgG-peroxidase-conjugated secondary antibody (Sigma, St. Louis, MO) with a dilution of 1:150, washed in PBS for 10 minutes, incubated with 0.5 mg/ml diaminobenzidine tetrahydrochloride 2-hydrate and 0.05% H2O2 for 10 minutes, and again washed in PBS. Negative control sections were incubated with secondary antibody alone, stained with hematoxylin, dehydrated, mounted, and viewed by light microscopy.21
Gene Expression of Proinflammatory Mediators
The localization and optical density of mRNA levels of ICAM-1, MCP-1, and TNF- were detected by quantitative in situ hybridization. Coronal cryostat sections (16 µm) were fixed in 4% formaldehyde for 10 minutes, washed with phosphate buffer (pH 7.4), and incubated in 0.25% acetic anhydride in 0.1 mol/L TE-HCl for 10 minutes. Sections were then hybridized (overnight at 45°C) with a random primed 35S-dATP-labeled ICAM-1, MCP-1, or TNF- cDNA-probe (American Type Culture Collection, Rockville, MD). Sections were washed, dried, and subsequently exposed to Kodak Biomax X-ray film (Eastman-Kodak, Rochester, NY). After exposure, film was developed and sections stained with hematoxylin and eosin (H&E). Quantification of mRNA density in the heart was performed using a computer image analysis system (NIH Image, 1.60) as previously reported.35
Sections stained with H&E were overlapped with radiographical film and examined under light microscopy to determine the distribution of detected mRNA.
Inflammatory Cell Responses
Cell proliferation and monocyte and lymphocyte infiltration were detected by immunohistochemical BrdU, ED-1, and T-cell labeling, respectively. BrdU is incorporated into DNA during the S-phase of the cell cycle. Cryostat sections (6 µm) were incubated with primary BrdU antibody (Sigma, St. Louis, MO) at a dilution of 1:1000; anti-ED-1 antibody (Harlan Bioproducts for Science, Indianapolis, IN) at a dilution of 1:140 or anti-T-cell antibody (ABCAM, Cambridge, UK) at a dilution of 1:200 in PBS containing 1% bovine serum albumin for 30 minutes. Sections were then incubated with IgG-peroxidase-conjugated secondary antibody (Sigma) with dilution of 1:150. Negative control sections were incubated with secondary antibody alone.21
Cardiac Morphology
Cryostat sections (6 µm) of heart were prepared to determine morphology by H&E and fibrillar collagen accumulation by collagen-specific picrosirius red staining and observed by light microscopy as previously reported.33 Collagen volume fraction of each section (total three sections/heart) was determined using a computer image analyzing system (NIH image, 1.60) as previously reported.35
Systolic Blood Pressure
Systolic blood pressure was measured at sacrifice representing week 3, 4, or 5 of treatment and in controls by tail cuff method, as previously reported.36
Statistical Analysis
Statistical analysis of in situ hybridization and systolic blood pressure findings was performed using analysis of variance. Values are expressed as mean ± SEM with P < 0.01 considered significant. Multiple group comparisons among controls and each group were made by Scheffé’s F-test.
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Results |
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NADPH oxidase catalyzes the one-electron reduction of molecular oxygen to superoxide anion, which can react with nitric oxide to form short-lived peroxynitrite. Peroxynitrite forms stable 3-nitrotyrosine-conjugated protein moieties.37
To investigate the role of oxidative stress associated with ALDO/salt treatment, we analyzed NADPH oxidase expression and activity in ALDO-treated rat hearts. Expression of NADPH oxidase was determined by immunohistochemical detection of the heme-bearing subunit (gp91phox), and 3-nitrotyrosine staining was monitored as a biomarker of oxidative/nitrosative stress. In ALDO-treated rats, gp91phox labeling was first observed within the perivascular space and at microscopic sites of repair during week 4 (Figure 1A)
and week 5 of ALDO treatment. Cells expressing gp91phox at these sites were primarily inflammatory and endothelial cells. Oxidase activation, as detected by 3-nitrotyrosine staining, was not seen at week 3 of treatment or in the normal myocardium of untreated controls (not shown). However, 3-nitrotyrosine staining was observed in inflammatory and endothelial cells in the perivascular space and microscopic sites of injury (Figure 1B)
in the heart at week 4 and 5 of ALDO/salt treatment.
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B Activation
The NF-B heterodimer normally remains in an inactive form bound to its inhibitory protein subunit IB. On stimulation, phosphorylated IB is degraded allowing NF-B to translocate from the cytosol into the cell nucleus, where it binds to promoter regions to initiate transcription of specific genes that encode host defense responses.38
The presence of activated NF-B (ie, its p65 subunit or RelA) can be detected by immunohistochemistry. In the present study, cardiac RelA labeling was negative in control rats and rats with 3 weeks of ALDO/salt treatment (not shown); however, it was positive at sites of repair in both right and left ventricles after 4 and 5 weeks treatment (Figure 1)
, where it was found primarily in vascular endothelial cells and inflammatory cells (Figure 1C)
at vascular and nonvascular sites of inflammation (see below).
Gene Expression of Proinflammatory Mediators
As detected by quantitative in situ hybridization (Figure 2)
, low optical density ICAM-1, MCP-1, and TNF- mRNA expression was observed in both right and left ventricles of control rats (Figure 2; A, D, G)
and those who received 3 weeks of ALDO/salt treatment (not shown). At 4 weeks of ALDO treatment, gene expression of ICAM-1 (Figure 2B)
, MCP-1 (Figure 2E)
, and TNF- (Figure 2H)
were markedly increased within the perivascular space of intramural coronary arteries and at sites of microscopic scarring found in both ventricles. The mRNA expression of these proinflammatory mediators remained elevated at these sites at week 5 of continued ALDO/salt treatment (not shown). This contrasts to ICAM-1, MCP-1, and TNF- gene expression in noninjured myocardium that remained no different from control hearts. Quantitative optical density of cardiac ICAM-1, MCP-1, and TNF- gene expression is shown in Figures 3, 4, and 5
, respectively.
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At sites of repair, infiltrating monocytes differentiate into macrophages and express ED-1. By immunohistochemistry, macrophages and lymphocytes were not observed in the heart of untreated controls or those with 3 weeks ALDO treatment (not shown). However, at weeks 4 and 5 of treatment, macrophages (Figure 1D)
and T cells (not shown) were observed within the perivascular space of intramyocardial coronary arteries and at sites of myocardial injury.
Vascular endothelial cell, smooth muscle cell, and fibroblast-like cell proliferation are a feature of repair tissue, which contributes to angiogenesis and collagen formation. By immunohistochemical detection of BrdU labeling, abundant proliferating cells were observed within the perivascular space and at microscopic sites of repair at week 4 (Figure 1E)
and week 5 of ALDO/salt treatment, but not at week 3.
Histochemical detection of fibrillar collagen by picrosirius red staining revealed an accumulation of collagen within the perivascular space of intramural coronary arteries and at sites of scarring that replaced lost myocytes during week 4 of ALDO/salt treatment, which resulted in increased collagen volume fraction (Figure 6)
. This perivascular fibrosis and microscopic scarring, which was not seen at week 3 of treatment or in untreated controls, became more evident at week 5 of continued ALDO treatment.
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Four weeks of Spi co-treatment abrogated the ALDO/salt-induced activation of NADPH oxidase and NF-B. Transcription of ICAM-1, MCP-1, and TNF-; inflammatory cell response; and the appearance of fibrosis in the heart were also significantly attenuated by Spi co-treatment. Quantitative data for gene expression of proinflammatory mediators and cardiac fibrosis are presented in Figures 2 to 6
, respectively.
Co-treatment with either PDTC or NAC also prevented ALDO/salt-induced NADPH oxidase and NF-B activation (not shown). Cardiac gene expression of ICAM-1, MCP-1, and TNF- in ALDO-treated animals was also primarily attenuated. These data are shown in Figures 2 to 5
, respectively. Inflammatory cell infiltration and cell proliferation in ALDO-treated rats were abrogated by co-treatment with either PDTC or NAC (not shown). Collagen volume fraction of the ventricles was markedly attenuated in rats receiving ALDO plus PDTC or ALDO plus NAC (Figure 6)
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Compared to controls, systolic blood pressure in ALDO-treated rats was elevated at each time point (Table 1)
and confirms previous findings.39
For the dose selected and as previously reported,39
Spi treatment normalized blood pressure, whereas PDTC and NAC partially suppressed systolic blood pressure (Table 1)
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Discussion |
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First is the coupling of an inflammatory response to ALDO-/salt-mediated induction of oxidative stress. Superoxide generation is related to an NADH/NADPH oxidase present in inflammatory cells and in endothelial cells and adventitial fibroblasts of vascular tissue.9,10,40-43
NADPH-oxidase expression, as assessed by gp91phox labeling and suggestive of enhanced superoxide production, was elevated at sites of vascular and nonvascular repair seen in both the left and right ventricles in rats treated with ALDO/salt for 4 and 5 weeks. Furthermore, staining of 3-nitrotyrosine at sites of cardiac repair provided indirect evidence of superoxide generation. Co-treatment with Spi, an ALDO receptor antagonist, or two different antioxidants, PDTC or NAC, each abrogated this response at vascular and nonvascular sites of cardiac injury. In a deoxycorticosterone acetate/salt model, another model of chronic mineralocorticoid excess antioxidant treatment proved renoprotective by attenuating NF-B activation and inflammatory cell invasion in renal parenchyma.44
What induces oxidative stress in rats treated with ALDO/salt remains unknown. Elevated arterial pressure has been held responsible for enhanced oxygen radical production by aortic tissue in rats with acquired or genetic hypertension.11-13,25,45 However, normotensive tissues (eg, pulmonary artery and right ventricle) have not been examined and the hypertension induced by systemic administration of norepinephrine was not associated with oxidative stress.12 Superoxide production has been observed in arterioles and postcapillary venules of Dahl salt-sensitive hypertensive rats and rats receiving a pressor dose of angiotensin II,11,22 in which elevations in intraluminal pressure do not reach these segments of the vasculature. Activated immune cells, not blood pressure, have been incriminated in initiating oxidative stress in Dahl salt-sensitive hypertensive rats.46,47 Therefore, the role of hemodynamic factors in these models remains uncertain. An elevation in arterial pressure is expected in the ALDO/salt model. This confounding variable raises the question of whether hemodynamic factors are involved in promoting the proinflammatory vascular phenotype in response to ALDO/salt treatment. A series of studies conducted throughout the past decade favors the importance of the circulating hormone (plus salt). The adverse structural remodeling of the coronary vasculature appears throughout the heart when circulating levels of ALDO are chronically increased, from either endogenous or exogenous sources. This includes the normotensive right atria and ventricle and left atrium.33,48 Arterial hypertension induced by infrarenal abdominal aortic banding is not accompanied by a remodeling of intramyocardial coronary arteries.33 Neither treatment with ALDO plus dietary salt deprivation nor high dietary salt treatment alone leads to this vascular remodeling.49 Furthermore, treatment with an mineralocorticoid receptor antagonist has proven cardioprotective. Given systemically, in either nondepressor or depressor dosages, together with ALDO/salt, such an agent prevents vascular remodeling independent of an elevation in arterial pressure.49 In the present study, we selected a 200-mg/kg/day dose of Spi, which our previous studies have demonstrated is a depressor dose.49 When a mineralocorticoid receptor antagonist is infused into a cerebral ventricle, it prevents the appearance of hypertension that accompanies the systemic administration of ALDO/salt, but not cardiac fibrosis.50,51 We therefore would conclude that the signal that initiates an up-regulation of oxidative stress in the ALDO/salt model remains unknown, but is not arterial hypertension. We might hypothesize a Na+-dependent effect of ALDO that promotes Mg2+ efflux from lymphocytes52 with subsequent [Mg2+]i deficiency and reduced (Mg2+-dependent) Na,K-ATPase activity leading to an elevation in [Na+]i and [Ca2+]i. Intracellular Ca2+ loading is a major determinant to the induction of oxidative stress in peripheral blood mononuclear cells, as is Mg2+ deficiency.53 We are currently exploring this hypothesis.
Our second major finding demonstrated rats treated with ALDO/salt for 4 and 5 weeks (but not 3 weeks) was accompanied by activation of NADPH oxidase and redox-sensitive NF-B, a central mediator of an inflammatory response and several proinflammatory mediators, which it regulates. Included with NF-B activation is an increased gene expression of an adhesion molecule, a chemokine, and a proinflammatory cytokine (ICAM-1, MCP-1, and TNF-, respectively). NF-B activation appeared at week 4 of ALDO/salt treatment and was localized to endothelial cells of intramural coronary arteries and arterioles and infiltrating inflammatory cells. Activation of this redox-sensitive transcription factor remained elevated at week 5 of ALDO/salt administration indicating it was not desensitized or down-regulated. An activation of oxidative stress leading to inflammatory responses has been proposed as contributing to the progressive nature of heart failure.5
Elevations in circulating levels of proinflammatory cytokines (eg, TNF- and interleukin-6), together with elevated plasma levels of ALDO, are recognized features of heart failure of diverse etiological origins.54-63
These cytokines adversely influence myocardial and cardiac myocyte contractility62
and contribute to a catabolic state that besets diverse organs.15,55,64
Lastly, this study has demonstrated that the ALDO/salt-induced proinflammatory phenotype is a necessary requisite to the accumulation of fibrous tissue at vascular and nonvascular sites of injury in the heart. Spi, PDTC, and NAC each prevented the appearance of this phenotype, including the expression of a cascade of effector proteins that contribute to the homing and transmigration of circulating monocytes/macrophages and T cells into injured vascular and nonvascular sites of cardiac tissue. The necessary role of inflammatory cells in promoting subsequent fibrosis has previously been reported by Nicoletti and co-workers65,66 in rats with genetic hypertension.
The importance of ALDO in the pathophysiology of salt and water retention in congestive heart failure is well established.67 In a recently reported, controlled clinical trial (RALES) conducted in 19 countries on 5 continents, using either Spi or placebo, in combination with ACE inhibitor and loop diuretic, a favorable impact in reducing all-cause mortality and cardiac mortality was observed in patients with severe heart failure.68 Findings of the present study may offer an additional perspective to the favorable response to Spi. The cardioprotective response we observed in response to either Spi or an antioxidant implicates oxidative stress in response to inappropriate elevations in circulating ALDO. Superoxide production reduces nitric oxide bioactivity while reducing the expression of nitric oxide synthase.26,69 Aldosteronism therefore predisposes to endothelial dysfunction, which has been observed in patients with heart failure and individuals with ALDO-producing adrenal adenoma and that was reversed by either Spi or surgical resection of the tumor.30,70 Moreover, and as reaffirmed in our study, systemic treatment with an ALDO receptor antagonist prevented cardiac remodeling by fibrillar collagen.49-51 In a substudy to the RALES trial, Zannad and colleagues71 found a reduction in elevated serological levels of markers of collagen synthesis in those individuals randomized to Spi, which accounted for the observed survival benefit not seen in those receiving placebo.
In summary, chronic ALDO/salt treatment is accompanied by a proinflammatory/fibrogenic phenotype involving the intramural coronary circulation and myocardium of both right and left ventricles and which is based on induction of oxidative/nitrosative stress (NADPH oxidase and 3-nitrotyrosine protein expression) at these vascular and nonvascular sites of injury. Activation of redox-sensitive NF-B, which transactivates the expression of proinflammatory mediators, appears in endothelial cells of the involved coronary vasculature and is persistent during continued ALDO/salt treatment. The proinflammatory cardiac phenotype is requisite to the appearance of fibrosis at these sites. Spi, PDTC, NAC each attenuate these responses suggesting ALDO-induced oxidative/nitrosative stress is involved in triggering this phenotype through a signaling pathway that remains to be identified.
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Acknowledgements |
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Footnotes |
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Supported, in part, by the National Heart, Lung, and Blood Institute (R01-HL67888 to Y. S., R01-HL6229 to K. T. W., and R01-HL66575).
Accepted for publication August 2, 2002.
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R. P. Brandes Avoiding Vicious Circles: Mineralocorticoid Receptor Antagonism Prevents Vascular Oxidative Stress Early After Myocardial Infarction Hypertension, November 1, 2007; 50(5): 842 - 843. [Full Text] [PDF]
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A. J. Rickard, J. W. Funder, J. Morgan, P. J. Fuller, and M. J. Young Does Glucocorticoid Receptor Blockade Exacerbate Tissue Damage after Mineralocorticoid/Salt Administration? Endocrinology, October 1, 2007; 148(10): 4829 - 4835. [Abstract] [Full Text] [PDF]
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S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
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M. Thomas, A. Vidal, S. K. Bhattacharya, R. A. Ahokas, Y. Sun, I. C. Gerling, and K. T. Weber Zinc dyshomeostasis in rats with aldosteronism. Response to spironolactone Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2361 - H2366. [Abstract] [Full Text] [PDF]
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 Jun Yuan, Ruhan Jia, and Yan Bao Beneficial effects of spironolactone on glomerular injury in streptozotocin-induced diabetic rats Journal of Renin-Angiotensin-Aldosterone System, September 1, 2007; 8(3): 118 - 126. [Abstract] [PDF]
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N. K. LeBrasseur, T.-A. S. Duhaney, D. S. De Silva, L. Cui, P. C. Ip, L. Joseph, and F. Sam Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension Hypertension, September 1, 2007; 50(3): 489 - 496. [Abstract] [Full Text] [PDF]
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S. Stas, A. Whaley-Connell, J. Habibi, L. Appesh, M. R. Hayden, P. R. Karuparthi, M. Qazi, E. M. Morris, S. A. Cooper, C. D. Link, et al. Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin-Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling Endocrinology, August 1, 2007; 148(8): 3773 - 3780. [Abstract] [Full Text] [PDF]
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Y. Hirono, T. Yoshimoto, N. Suzuki, T. Sugiyama, M. Sakurada, S. Takai, N. Kobayashi, M. Shichiri, and Y. Hirata 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, April 1, 2007; 148(4): 1688 - 1696. [Abstract] [Full Text] [PDF]
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G. Fejes-Toth and A. Naray-Fejes-Toth Early Aldosterone-Regulated Genes in Cardiomyocytes: Clues to Cardiac Remodeling? Endocrinology, April 1, 2007; 148(4): 1502 - 1510. [Abstract] [Full Text] [PDF]
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M. R. Bergman, J. R. Teerlink, R. Mahimkar, L. Li, B.-Q. Zhu, A. Nguyen, S. Dahi, J. S. Karliner, and D. H. Lovett Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1847 - H1860. [Abstract] [Full Text] [PDF]
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H. Peng, O. A. Carretero, T.-D. Liao, E. L. Peterson, and N.-E. Rhaleb Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension Hypertension, March 1, 2007; 49(3): 695 - 703. [Abstract] [Full Text] [PDF]
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P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
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Wenxia Chai, Y. M Hoedemaekers, R. H. van Schaik, M. van Fessem, I. M Garrelds, J. J Saris, D. Dooijes, F. J ten Cate, M. M. Kofflard, and A. J. Danser Cardiac aldosterone in subjects with hypertrophic cardiomyopathy Journal of Renin-Angiotensin-Aldosterone System, December 1, 2006; 7(4): 225 - 230. [Abstract] [PDF]
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A. J. Rickard, J. W. Funder, P. J. Fuller, and M. J. Young The Role of the Glucocorticoid Receptor in Mineralocorticoid/Salt-Mediated Cardiac Fibrosis Endocrinology, December 1, 2006; 147(12): 5901 - 5906. [Abstract] [Full Text] [PDF]
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J. M. Luther, J. V. Gainer, L. J. Murphey, C. Yu, D. E. Vaughan, J. D. Morrow, and N. J. Brown Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor-Dependent Mechanism Hypertension, December 1, 2006; 48(6): 1050 - 1057. [Abstract] [Full Text] [PDF]
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 M. Rahman, A. Nishiyama, P. Guo, Y. Nagai, G.-X. Zhang, Y. Fujisawa, Y.-Y. Fan, S. Kimura, N. Hosomi, K. Omori, et al. Effects of Adrenomedullin on Cardiac Oxidative Stress and Collagen Accumulation in Aldosterone-Dependent Malignant Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1323 - 1329. [Abstract] [Full Text] [PDF]
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C. E. Murdoch, M. Zhang, A. C. Cave, and A. M. Shah NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure Cardiovasc Res, July 15, 2006; 71(2): 208 - 215. [Abstract] [Full Text] [PDF]
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Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber Oxidative stress in aldosteronism Cardiovasc Res, July 15, 2006; 71(2): 300 - 309. [Abstract] [Full Text] [PDF]
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 M Satoh, Y Ishikawa, Y Minami, T Akatsu, and M Nakamura Eplerenone inhibits tumour necrosis factor alpha shedding process by tumour necrosis factor alpha converting enzyme in monocytes from patients with congestive heart failure. Heart, July 1, 2006; 92(7): 979 - 980. [Full Text] [PDF]
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 S. Johar, A. C. Cave, A. Narayanapanicker, D. J. Grieve, and A. M. Shah Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase FASEB J, July 1, 2006; 20(9): 1546 - 1548. [Abstract] [Full Text] [PDF]
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W. Zhao, R. A. Ahokas, K. T. Weber, and Y. Sun ANG II-induced cardiac molecular and cellular events: role of aldosterone Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H336 - H343. [Abstract] [Full Text] [PDF]
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T. A. Williams, A. Verhovez, A. Milan, F. Veglio, and P. Mulatero Protective Effect of Spironolactone on Endothelial Cell Apoptosis Endocrinology, May 1, 2006; 147(5): 2496 - 2505. [Abstract] [Full Text] [PDF]
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 S.-Y. Han, C.-H. Kim, H.-S. Kim, Y.-H. Jee, H.-K. Song, M.-H. Lee, K.-H. Han, H.-K. Kim, Y.-S. Kang, J.-Y. Han, et al. Spironolactone Prevents Diabetic Nephropathy through an Anti-Inflammatory Mechanism in Type 2 Diabetic Rats J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1362 - 1372. [Abstract] [Full Text] [PDF]
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Y.-M. Cha, P. P. Dzeja, M. M. Redfield, W. K. Shen, and A. Terzic Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1686 - H1692. [Abstract] [Full Text] [PDF]
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N. Kobayashi, K. Yoshida, S. Nakano, T. Ohno, T. Honda, Y. Tsubokou, and H. Matsuoka Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts Hypertension, April 1, 2006; 47(4): 671 - 679. [Abstract] [Full Text] [PDF]
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N. C Shah, S. Pringle, and A. Struthers Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2006; 7(1): 20 - 30. [Abstract] [PDF]
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A. Vidal, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, I. C. Gerling, and K. T. Weber Calcium paradox of aldosteronism and the role of the parathyroid glands Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H286 - H294. [Abstract] [Full Text] [PDF]
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P. J. Fuller and M. J. Young Mechanisms of Mineralocorticoid Action Hypertension, December 1, 2005; 46(6): 1227 - 1235. [Abstract] [Full Text] [PDF]
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S. Takai, D. Jin, M. Muramatsu, K. Kirimura, H. Sakonjo, and M. Miyazaki Eplerenone Inhibits Atherosclerosis in Nonhuman Primates Hypertension, November 1, 2005; 46(5): 1135 - 1139. [Abstract] [Full Text] [PDF]
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S. Keidar, A. Gamliel-Lazarovich, M. Kaplan, E. Pavlotzky, S. Hamoud, T. Hayek, R. Karry, and Z. Abassi Mineralocorticoid Receptor Blocker Increases Angiotensin-Converting Enzyme 2 Activity in Congestive Heart Failure Patients Circ. Res., October 28, 2005; 97(9): 946 - 953. [Abstract] [Full Text] [PDF]
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I. Cucoranu, R. Clempus, A. Dikalova, P. J. Phelan, S. Ariyan, S. Dikalov, and D. Sorescu NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-{beta}1-Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts Circ. Res., October 28, 2005; 97(9): 900 - 907. [Abstract] [Full Text] [PDF]
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K. Miyata, M. Rahman, T. Shokoji, Y. Nagai, G.-X. Zhang, G.-P. Sun, S. Kimura, T. Yukimura, H. Kiyomoto, M. Kohno, et al. Aldosterone Stimulates Reactive Oxygen Species Production through Activation of NADPH Oxidase in Rat Mesangial Cells J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2906 - 2912. [Abstract] [Full Text] [PDF]
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W. Chai, I. M. Garrelds, R. de Vries, W. W. Batenburg, J. P. van Kats, and A.H. Jan Danser Nongenomic Effects of Aldosterone in the Human Heart: Interaction With Angiotensin II Hypertension, October 1, 2005; 46(4): 701 - 706. [Abstract] [Full Text] [PDF]
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G. E. Callera, A. C. I. Montezano, A. Yogi, R. C. Tostes, Y. He, E. L. Schiffrin, and R. M. Touyz c-Src-Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats Hypertension, October 1, 2005; 46(4): 1032 - 1038. [Abstract] [Full Text] [PDF]
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M. K. Rude, T.-A. S. Duhaney, G. M. Kuster, S. Judge, J. Heo, W. S. Colucci, D. A. Siwik, and F. Sam Aldosterone Stimulates Matrix Metalloproteinases and Reactive Oxygen Species in Adult Rat Ventricular Cardiomyocytes Hypertension, September 1, 2005; 46(3): 555 - 561. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz Calcium, Magnesium, and Oxidative Stress in Hyperaldosteronism Circulation, February 22, 2005; 111(7): 830 - 831. [Full Text] [PDF]
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V. S. Chhokar, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, L. K. Myers, Z. Xing, R. A. Smith, I. C. Gerling, and K. T. Weber Hyperparathyroidism and the Calcium Paradox of Aldosteronism Circulation, February 22, 2005; 111(7): 871 - 878. [Abstract] [Full Text] [PDF]
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G. M. Kuster, E. Kotlyar, M. K. Rude, D. A. Siwik, R. Liao, W. S. Colucci, and F. Sam Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload Circulation, February 1, 2005; 111(4): 420 - 427. [Abstract] [Full Text] [PDF]
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R. A. Ahokas, Y. Sun, S. K. Bhattacharya, I. C. Gerling, and K. T. Weber Aldosteronism and a Proinflammatory Vascular Phenotype: Role of Mg2+, Ca2+, and H2O2 in Peripheral Blood Mononuclear Cells Circulation, January 4, 2005; 111(1): 51 - 57. [Abstract] [Full Text] [PDF]
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J. Asbun, A. M. Manso, and F. J. Villarreal Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H227 - H234. [Abstract] [Full Text] [PDF]
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K. T. Weber The neuroendocrine-immune interface gone awry in aldosteronism Cardiovasc Res, December 1, 2004; 64(3): 381 - 383. [Full Text] [PDF]
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V. S. Chhokar, Y. Sun, S. K. Bhattacharya, R. A. Ahokas, L. K. Myers, Z. Xing, R. A. Smith, I. C. Gerling, and K. T. Weber Loss of bone minerals and strength in rats with aldosteronism Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2023 - H2026. [Abstract] [Full Text] [PDF]
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J. Lebowitz, R. S. Edinger, B. An, C. J. Perry, S. Onate, T. R. Kleyman, and J. P. Johnson I{kappa}B Kinase-{beta} (IKK{beta}) Modulation of Epithelial Sodium Channel Activity J. Biol. Chem., October 1, 2004; 279(40): 41985 - 41990. [Abstract] [Full Text] [PDF]
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S. Nakamura, M. Yoshimura, M. Nakayama, T. Ito, Y. Mizuno, E. Harada, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Possible Association of Heart Failure Status With Synthetic Balance Between Aldosterone and Dehydroepiandrosterone in Human Heart Circulation, September 28, 2004; 110(13): 1787 - 1793. [Abstract] [Full Text] [PDF]
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A. Garnier, J. K. Bendall, S. Fuchs, B. Escoubet, F. Rochais, J. Hoerter, J. Nehme, M.-L. Ambroisine, N. De Angelis, G. Morineau, et al. Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase-Transgenic Mice Circulation, September 28, 2004; 110(13): 1819 - 1825. [Abstract] [Full Text] [PDF]
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M. Young and J. W. Funder Eplerenone, But Not Steroid Withdrawal, Reverses Cardiac Fibrosis in Deoxycorticosterone/ Salt-Treated Rats Endocrinology, July 1, 2004; 145(7): 3153 - 3157. [Abstract] [Full Text] [PDF]
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M. Nian, P. Lee, N. Khaper, and P. Liu Inflammatory Cytokines and Postmyocardial Infarction Remodeling Circ. Res., June 25, 2004; 94(12): 1543 - 1553. [Abstract] [Full Text] [PDF]
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I. Mazak, A. Fiebeler, D. N. Muller, J.-K. Park, E. Shagdarsuren, C. Lindschau, R. Dechend, C. Viedt, B. Pilz, H. Haller, et al. Aldosterone Potentiates Angiotensin II-Induced Signaling in Vascular Smooth Muscle Cells Circulation, June 8, 2004; 109(22): 2792 - 2800. [Abstract] [Full Text] [PDF]
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I. Juknevicius, Y. Segal, S. Kren, R. Lee, and T. H. Hostetter Effect of aldosterone on renal transforming growth factor-{beta} Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1059 - F1062. [Abstract] [Full Text] [PDF]
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D. H. Endemann, R. M. Touyz, M. Iglarz, C. Savoia, and E. L. Schiffrin Eplerenone Prevents Salt-Induced Vascular Remodeling and Cardiac Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, June 1, 2004; 43(6): 1252 - 1257. [Abstract] [Full Text] [PDF]
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S. Keidar, M. Kaplan, E. Pavlotzky, R. Coleman, T. Hayek, S. Hamoud, and M. Aviram 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, May 11, 2004; 109(18): 2213 - 2220. [Abstract] [Full Text] [PDF]
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F. Michel, M.-L. Ambroisine, M. Duriez, C. Delcayre, B. I. Levy, and J.-S. Silvestre Aldosterone Enhances Ischemia-Induced Neovascularization Through Angiotensin II-Dependent Pathway Circulation, April 27, 2004; 109(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
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A. Nishiyama, L. Yao, Y. Nagai, K. Miyata, M. Yoshizumi, S. Kagami, S. Kondo, H. Kiyomoto, T. Shokoji, S. Kimura, et al. Possible Contributions of Reactive Oxygen Species and Mitogen-Activated Protein Kinase to Renal Injury in Aldosterone/Salt-Induced Hypertensive Rats Hypertension, April 1, 2004; 43(4): 841 - 848. [Abstract] [Full Text] [PDF]
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K. T. Weber From Inflammation to Fibrosis: A Stiff Stretch of Highway Hypertension, April 1, 2004; 43(4): 716 - 719. [Full Text] [PDF]
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F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
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P. Mulatero, M. Stowasser, K.-C. Loh, C. E. Fardella, R. D. Gordon, L. Mosso, C. E. Gomez-Sanchez, F. Veglio, and W. F. Young Jr. Increased Diagnosis of Primary Aldosteronism, Including Surgically Correctable Forms, in Centers from Five Continents J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1045 - 1050. [Abstract] [Full Text] [PDF]
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A. D Struthers Aldosterone blockade in heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S23 - S27. [Abstract] [PDF]
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E. M. Oestreicher, D. Martinez-Vasquez, J. R. Stone, L. Jonasson, W. Roubsanthisuk, K. Mukasa, and G. K. Adler 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, November 18, 2003; 108(20): 2517 - 2523. [Abstract] [Full Text] [PDF]
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R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface Circ. Res., November 14, 2003; 93 (10): e124 - e135. [Abstract] [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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T. H. Hostetter and H. N. Ibrahim Aldosterone in Chronic Kidney and Cardiac Disease J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2395 - 2401. [Abstract] [Full Text] [PDF]
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I. C. Gerling, Y. Sun, R. A. Ahokas, L. A. Wodi, S. K. Bhattacharya, K. J. Warrington, A. E. Postlethwaite, and K. T. Weber Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H813 - H821. [Abstract] [Full Text] [PDF]
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