Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause

2008 ◽  
Vol 295 (4) ◽  
pp. H1481-H1488 ◽  
Author(s):  
Talin Ebrahimian ◽  
M. Ram Sairam ◽  
Ernesto L. Schiffrin ◽  
Rhian M. Touyz
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Receptor Expression ◽  
Ang Ii ◽  
Antioxidant Function ◽  
Endogenous Antioxidant

Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. TRX is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild-type (WT) and follitropin receptor knockout (FORKO) mice (20–24 wk), with hormonal imbalances, were studied. Mice were infused with ANG II (400 ng·kg−1·min−1; 14 days). Systolic blood pressure was increased by ANG II in WT (166 ± 8 vs. 121 ± 5 mmHg) and FORKO (176 ± 7 vs. 115 ± 5 mmHg; P < 0.0001; n = 9/group) mice. In ANG II-infused FORKO mice, cardiac mass was increased by 42% ( P < 0.001). This was associated with increased collagen content and augmented ERK1/2 phosphorylation (2-fold). Cardiac TRX expression and activity were decreased by ANG II in FORKO but not in WT ( P < 0.01) mice. ASK-1 expression, cleaved caspase III content, and Bax/Bcl-2 content were increased in ANG II-infused FORKO ( P < 0.05). ANG II had no effect on cardiac NAD(P)H oxidase activity or on O2•− levels in WT or FORKO. Cardiac ANG II type 1 receptor expression was similar in FORKO and WT. These findings indicate that in female FORKO, ANG II-induced cardiac hypertrophy and fibrosis are associated with the TRX downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of TRX may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

2008 ◽  
Vol 294 (2) ◽  
pp. H1058-H1066 ◽  
Author(s):  
Johannes Jacobi ◽  
Renke Maas ◽  
Nada Cordasic ◽  
Kilian Koch ◽  
Roland E. Schmieder ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Asymmetric Dimethylarginine ◽  
Interstitial Fibrosis ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Ang Ii ◽  
Renal Interstitial Fibrosis

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 μg·kg−1·min−1 ANG II, 3.0 μg·kg−1·min−1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.

Abstract 434: Sirt4 Accelerates Ang II-induced Pathological Cardiac Hypertrophy by Inhibiting Mnsod Activity

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Depei Liu ◽  
Yu-Xuan Luo ◽  
Xiaoqiang Tang ◽  
Xi-Zhou An ◽  
Xue-Min Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Manganese Superoxide Dismutase ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Hypertrophic Growth ◽  
Pathological Cardiac Hypertrophy

Aims: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. Methods and results: Male C57BL/6 Sirt4 knockout mice, transgenic mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analyzed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-transgenic mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with MnTBAP, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice. Conclusions: Sirt4 promotes hypertrophic growth and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.

Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression

2003 ◽  
Vol 285 (1) ◽  
pp. R117-R124 ◽  
Author(s):  
Tina Chabrashvili ◽  
Chagriya Kitiyakara ◽  
Jonathan Blau ◽  
Alex Karber ◽  
Shakil Aslam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Candesartan Cilexetil ◽  
Superoxide Dismutases ◽  
Protective Effects ◽  
Ang Ii

Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG type 1 vs. type 2 receptors (AT1-R and AT2-R, respectively) is unknown. We infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin F2α (8-Iso) and malonyldialdehyde (MDA) were related to renal cortical mRNA abundance for subunits of NADPH oxidase and superoxide dismutases (SODs) using real-time PCR. Subsets of ANG II-infused rats were given the AT1-R antagonist candesartan cilexetil (Cand) or the AT2-R antagonist PD-123,319 (PD). Compared to vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh, 5.4 ± 0.8 vs. ANG II, 7.6 ± 0.5 pg/24 h; P < 0.05). This was prevented by Cand (5.6 ± 0.5 pg/24 h; P < 0.05) and increased by PD (15.8 ± 2.0 pg/24 h; P < 0.005). There were similar changes in MDA excretion. Compared to Veh, ANG II significantly ( P < 0.005) increased the renal cortical mRNA expression of p22 phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold) and decreased expression of Nox-4 (2.1-fold) and extracellular (EC)-SOD (2.1-fold). Cand prevented all of these changes except for the increase in Mn-SOD. PD accentuated changes in p22 phox and Nox-1 and increased p67 phox. We conclude that ANG II infusion stimulates oxidative stress via AT1-R, which increases the renal cortical mRNA expression of p22 phox and Nox-1 and reduces abundance of Nox-4 and EC-SOD. This is offset by strong protective effects of AT2-R, which are accompanied by decreased expression of p22 phox, Nox-1, and p67 phox.

Hypertension in mice lacking the CXCR3 chemokine receptor

2009 ◽  
Vol 296 (4) ◽  
pp. F780-F789 ◽  
Author(s):  
Hsiang-Hao Hsu ◽  
Kerstin Duning ◽  
Hans Henning Meyer ◽  
Miriam Stölting ◽  
Thomas Weide ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Chemokine Receptor ◽  
Receptor Expression ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Vascular Contractility ◽  
Resistance Vessels ◽  
M3 Receptor

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3−/− mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3−/− mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3−/− mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.

Abstract 668: Inhibition of DNA Methyltransferase Inhibits the Ang II-Induced Increase in Blood Pressure, Vascular Remodeling and Target Organ Damage

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Methode Bacanamwo ◽  
Mukaila Akinbami ◽  
Dahai Wang ◽  
Gary H Gibbons
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Vascular Remodeling ◽  
Dna Methyltransferase ◽  
Target Organ Damage ◽  
Critical Role ◽  
Organ Damage ◽  
Target Organ ◽  
Ang Ii ◽  
Resistance Arteries

Growth signals stimulate DNA methyltransferase (DNMT) expression through extracellular signal-regulated kinases 1/2 (ERK1/2) pathway and that inhibition of ERK1/2 signaling results in repression of DNMT expression and activation of expression of some DNMT-repressed genes. Angiotensin II (Ang II) has been shown to stimulate ERK1/2 signaling in resistance arteries. We hypothesized that Ang II stimulates DNMT expression resulting in methylation and repression of antihypertensive genes such as 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and that blocking DNMT activity may inhibit Ang II-induced hypertension, vascular remodeling, and target organ damage. C57BL/6J (C57) mice were treated with the specific DNMT inhibitor 5′-aza-2′-deoxycytidine (aza-CdR, 1 mg/kg/day) intraperitoneally for 3 consecutive days before subcutaneous Ang II infusion for 28d at a pressure dose of 0.7 mg/kg/day using Alzet osmotic minipumps. Systolic blood pressure was monitored during this period and tissues were harvested to determine vascular wall thickness, cardiac hypertrophy, and expression and methylation of 11β-HSD2 in arteries and the kidneys. Ang II infusion induced a more than 2-fold increase in DNMT1 expression (n=6, p≤ 0.05). Moreover, blocking DNMT1 activity significantly inhibited the Ang II-induced increase in systolic and diastolic blood pressure (from 102 ± 3 to138 ± 7 for saline-treated vs. 101 ± 4 to 105 ± 6 mm Hg for aza-CdR-treated mice, n=8, p≤ 0.01 for saline vs.aza-CdR in the presence of Ang II treatment). In addition, expression of 11β-HSD2 was inhibited by Ang II treatment. However, expression of 11β-HSD2 was found to be above the background observed in absence of Ang II when Ang II treatment was associated with DNMT activity blockade. Methylation-specific PCR indicated that 11β-HSD2 was methylated in the arteries and kidneys but its Ang II-dependency is still to be determined. Finally when DNMT activity was inhibited, the Ang II-induced increase cardiac hypertrophy (heart/body weight) and wall/lumen ratio in the carotid arteries were significantly inhibited (n= 8, p≤ 0.05). These results suggest that DNA methylation plays a critical role in the coordinate regulation of genes involved in the pathogenesis of hypertension and vascular remodeling.

Abstract 097: EGF Receptor And ER Stress Mediate End-organ Damage But Not Hypertension Induced By Angiotensin II In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Katherine J Elliott ◽  
Toshiyuki Tsuji ◽  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Steven Forrester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Egf Receptor ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Egfr Activation ◽  
And Oxidative Stress

In cultured vascular smooth muscle cells (VSMC), a metalloprotease ADAM17-dependent EGF receptor (EGFR) activation mediates ERK1/2 activation and subsequent hypertrophy induced by angiotensin II (Ang II). Both ER and oxidative stress are implicated in hypertensive end-organ damage. We hypothesized that pharmacological inhibition of EGFR may prevent end-organ damage but not hypertension in mice infused with Ang II via suppression of ER/oxidative stress. To test this hypothesis, we have evaluated Ang II-induced end-organ damage as well as hypertension in C57Bl/6 mice with or without an EGFR inhibitor erlotinib (20mg/kg/day ip) or ER stress inhibitor 4-phenyl butyric acid (PBA: 1g/kg/day in drinking water). Upon Ang II infusion (1000 ng/kg/min) for 2 weeks, control mice showed phenotypes of cardiac hypertrophy including increased HW/BW ratio (mg/g: 7.9±0.7 vs 5.7±0.6 p<0.01 n=8) and increased LVPWd assessed by cardiac echo (mm: 0.98±0.14 vs 0.69±0.05, p<0.05 n=8) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, cardiac hypertrophy and vascular remodeling were attenuated in mice with Ang II plus erlotinib or PBA; HW/BW ratio (6.8±0.6 or 6.2±0.6 n=8), and cardiac echo (LVPWd: 0.65±0.07 or 0.80±0.07 n=8) compared with saline infusion. Renal fibrosis observed with Ang II infusion was also attenuated in mice with Ang II plus erotinib or PBA. However, Ang II induced similar levels of hypertension in non-treated, erlotinib-treated or PBA-treated mice assessed by telemetry (MAP mmHg: 144±9 vs 149±20 or 139±4). Ang II infusion in mice enhanced ADAM17 and phospho-Tyr EGFR staining in vasculatures of heart and kidney, whereas mice with Ang II plus erlotinib or PBA had diminished phospho-Tyr EGFR staining and no ADAM17 staining in the vasculatures. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused mice with erlotinib or PBA. These data suggest that EGFR activation and subsequent ER stress enhancement are critical for end organ damage via induction of ADAM17 and oxidative stress and is independent from blood pressure regulation.

scholarly journals Pathogenesis of Target Organ Damage in Hypertension: Role of Mitochondrial Oxidative Stress

2014 ◽  
Vol 16 (1) ◽  
pp. 823-839 ◽  
Author(s):  
Speranza Rubattu ◽  
Beniamino Pagliaro ◽  
Giorgia Pierelli ◽  
Caterina Santolamazza ◽  
Sara Di Castro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Mitochondrial Oxidative Stress

Abstract P618: Inactivation of Mitochondrial Deacetylase Sirt3 Promotes Vascular Oxidative Stress, Increases Endothelial Dysfunction and Exacerbates Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna E Dikalova ◽  
Roman Uzhachenko ◽  
Hana A Itani ◽  
David G Harrison ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Fold Increase ◽  
Organ Damage ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Oxidative Stress

Endothelial dysfunction is associated with aging, diabetes, hyperlipidemia, obesity and these risk factors affect the expression and activity of the mitochondrial deacetylase Sirt3. Sirt3 activates major antioxidant SOD2 by deacetylation of specific lysine residues and Sirt3 depletion increases oxidative stress. We hypothesized that loss of vascular Sirt3 increases endothelial dysfunction, promotes hypertension and end organ damage. The role of vascular Sirt3 was studied in wild-type C57Bl/6J mice and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ) using angiotensin II model of hypertension (Ang II, 0.7 mg/kg/day). Western blot showed 30% reduction of vascular Sirt3 and 2-fold increase in SOD2 acetylation in Ang II-infused WT mice. We have tested if ex vivo treatment of aorta with Sirt3 activator resveratrol improves endothelial function. Indeed, ex vivo incubation with resveratrol (10 μM) significantly reduced SOD2 acetylation, diminished mitochondrial O 2 and increased endothelial NO to normal level while Sirt3-inactive analog dihydroresveratrol had no effect. Specific role of vascular Sirt3 was studied in Smc Sirt3 KO mice by crossing floxed Sirt3 mice with mice carrying gene for inducible cre in the vascular smooth muscle. Sirt3 deletion exacerbates hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increases mortality in Ang II-infused Smc Sirt3 KO mice (60% vs 10% in wild-type) associated with severe edema and aortic aneurysm (100% vs 20% in wild-type). Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. Indeed, Ang II infusion increased vascular O 2 by 2-fold and reduced endothelial NO by 2-fold. Interestingly, Ang II infusion in Smc Sirt3 KO mice caused severe vascular oxidative stress (3-fold increase in O 2 ) and exacerbated endothelial dysfunction (4-fold decrease in NO). These data indicate that reduced vascular Sirt3 activity occurs in hypertension and this promotes vascular oxidative stress, increases endothelial dysfunction, exacerbates hypertension, increases end-organ-damage and mortality. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

scholarly journals Novel Therapeutic Effects of Pterosin B on Ang II-Induced Cardiomyocyte Hypertrophy

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5279
Author(s):  
Chang Youn Lee ◽  
Han Ki Park ◽  
Bok-Sim Lee ◽  
Seongtae Jeong ◽  
Sung-Ae Hyun ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Therapeutic Effects ◽  
Ang Ii ◽  
Pathological Cardiac Hypertrophy ◽  
Glycation End Products ◽  
Abnormal Increase

Pathological cardiac hypertrophy is characterized by an abnormal increase in cardiac muscle mass in the left ventricle, resulting in cardiac dysfunction. Although various therapeutic approaches are being continuously developed for heart failure, several studies have suggested natural compounds as novel potential strategies. Considering relevant compounds, we investigated a new role for Pterosin B for which the potential life-affecting biological and therapeutic effects on cardiomyocyte hypertrophy are not fully known. Thus, we investigated whether Pterosin B can regulate cardiomyocyte hypertrophy induced by angiotensin II (Ang II) using H9c2 cells. The antihypertrophic effect of Pterosin B was evaluated, and the results showed that it reduced hypertrophy-related gene expression, cell size, and protein synthesis. In addition, upon Ang II stimulation, Pterosin B attenuated the activation and expression of major receptors, Ang II type 1 receptor and a receptor for advanced glycation end products, by inhibiting the phosphorylation of PKC-ERK-NF-κB pathway signaling molecules. In addition, Pterosin B showed the ability to reduce excessive intracellular reactive oxygen species, critical mediators for cardiac hypertrophy upon Ang II exposure, by regulating the expression levels of NAD(P)H oxidase 2/4. Our results demonstrate the protective role of Pterosin B in cardiomyocyte hypertrophy, suggesting it is a potential therapeutic candidate.

scholarly journals 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 ◽  
Vol 148 (4) ◽  
pp. 1688-1696 ◽  
Author(s):  
Yuki Hirono ◽  
Takanobu Yoshimoto ◽  
Noriko Suzuki ◽  
Toru Sugiyama ◽  
Maya Sakurada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Renin Angiotensin System ◽  
Aortic Tissue ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.

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