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  • 1
    Online Resource
    Online Resource
    Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Hypertension Vol. 54, No. 2 ( 2009-08), p. 359-364
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 2 ( 2009-08), p. 359-364
    Abstract: Growth arrest–specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels. Mineralocorticoid receptor blockade prevented target organ damage and decreased the elevated Gas 6 expression. Vascular smooth muscle cells given aldosterone increased their Gas 6 expression in vitro. To test the pathophysiological relevance, we investigated the effects of deoxycorticosterone acetate (DOCA) on Gas 6 gene-deleted ( −/− ) mice. After 6 weeks DOCA, Gas 6 −/− mice developed similar telemetric blood pressure elevations compared to wild-type mice but were protected from cardiac hypertrophy. Cardiac expression of interleukin 6 and collagen IV was blunted in Gas 6 −/− mice, indicating reduced inflammation and fibrosis. Gas 6 −/− mice also had an improved renal function with reduced albuminuria, compared to wild-type mice. Renal fibrosis and fibronectin deposition in the kidney were also reduced. Gas 6 deficiency reduces the detrimental effects of aldosterone on cardiac and renal remodeling independent of blood pressure reduction. Gas 6 appears to play a role in mineralocorticoid receptor-mediated target organ damage. Furthermore, because warfarin interferes with Gas 6 protein expression, the findings could be of clinical relevance for anticoagulant choices.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.109.129460
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
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  • 2
    Online Resource
    Online Resource
    Abstract 515: Aldosterone Modulates Endothelial Paracellular Permeability by Opening Intercellular Junctions
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Hypertension Vol. 60, No. suppl_1 ( 2012-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 60, No. suppl_1 ( 2012-09)
    Abstract: Aldosterone (Ald) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Ald alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells (HUVEC) were exposed to Ald (10 -9 mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions, and activation of intracellular signaling pathways were determined. Ald increased endothelial paracellular permeability for molecules up to 70 kDa within 60 min. A transient loss of cortical actin with formation of actin stress fibers, and disruption of continuous adherens and tight junction strands, accompanied the changes. Mineralocorticoid receptor (MR) blockade, inhibition of RhoA or disruption of extracellular regulated protein kinase (ERK) 1/2 signaling pathways attenuated the Ald-related effects. Moreover, the observed changes of the actin cytoskeleton and intercellular junction architecture were accompanied by a rapid dephosphorylation of protein kinase B (AKT) as well as deactivation of endothelial NO synthase (eNOS). Ex vivo tracer flux experiments with Evans Blue (EB)-conjugated albumin demonstrated concordant response to Ald in freshly isolated umbilical arteries. In summary, Ald leads to increased permeability of endothelial monolayer or isolated arteries. These alterations are associated with a temporal opening of Intercellular junctions and diminished eNOS activity, and depend on activation of the RhoA/ERK pathway. We conclude that these mechanisms could contribute to Ald-induced vasculopathy.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.60.suppl_1.A515
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 3
    Online Resource
    Online Resource
    Cardiac gene expression profile in rats with terminal heart failure and cachexia
    American Physiological Society ; 2005
    In:  Physiological Genomics Vol. 20, No. 3 ( 2005-02-10), p. 256-267
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 20, No. 3 ( 2005-02-10), p. 256-267
    Abstract: About one-half of double transgenic rats (dTGR) overexpressing the human renin and angiotensinogen genes die by age 7 wk of terminal heart failure (THF); the other (preterminal) one-half develop cardiac damage but survive. Our study’s aim was to elucidate cardiac gene expression differences in dTGR-THF compared with dTGR showing compensated cardiac hypertrophy but not yet THF. dTGR treated with losartan (LOS) and nontransgenic rats (SD) served as controls. THF-dTGR body weight was significantly lower than for all other groups. At death, THF-dTGR had blood pressures of 228 ± 7 mmHg (cardiac hypertrophy index 6.2 ± 0.1 mg/g). Tissue Doppler showed reduced peak early (Ea) to late (Aa) diastolic expansion in THF-dTGR, indicating diastolic function. Preterminal dTGR had blood pressures of 197 ± 5 mmHg (cardiac hypertrophy index 5.1 ± 0.1 mg/g); Ea 〈 Aa compared with LOS-dTGR (141 ± 6 mmHg; 3.7±0.1 mg/g; Ea 〉 Aa) and SD (112 ± 4 mmHg; 3.6 ± 0.1 mg/g; Ea 〉 Aa). Left ventricular RNA was isolated for the Affymetrix system and TaqMan RT-PCR. THF-dTGR and dTGR showed upregulation of hypertrophy markers and α/β-myosin heavy chain switch to the fetal isoform. THF-dTGR (vs. dTGR) showed upregulation of 239 and downregulation of 150 genes. Various genes of mitochodrial respiratory chain and lipid catabolism were reduced. In addition, genes encoding transcription factors (CEBP-β, c-fos, Fra-1), coagulation, remodeling/repair components (HSP70, HSP27, heme oxygenase), immune system (complement components, IL-6), and metabolic pathway were differentially expressed. In contrast, LOS-dTGR and SD had similar expression profiles. These data demonstrate that THF-dTGR show an altered expression profile compared with preterminal dTGR.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00165.2004
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
    detail.hit.zdb_id: 2031330-5
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  • 4
    Online Resource
    Online Resource
    Statins Attenuate Ischemia-Reperfusion Injury by Inducing Heme Oxygenase-1 in Infiltrating Macrophages
    Elsevier BV ; 2007
    In:  The American Journal of Pathology Vol. 170, No. 4 ( 2007-04), p. 1192-1199
    Details
    In: The American Journal of Pathology, Elsevier BV, Vol. 170, No. 4 ( 2007-04), p. 1192-1199
    Type of Medium: Online Resource
    ISSN: 0002-9440
    URL: Article
    DOI: 10.2353/ajpath.2007.060782
    RVK:
    XA 10000
    RVK:
    XA 19800
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 1480207-7
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  • 5
    Online Resource
    Online Resource
    Glucocorticoid-Related Signaling Effects in Vascular Smooth Muscle Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Hypertension Vol. 51, No. 5 ( 2008-05), p. 1372-1378
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 5 ( 2008-05), p. 1372-1378
    Abstract: Mineralocorticoid receptor blockade protects from angiotensin II–induced target-organ damage. 11β-Hydroxysteroid dehydrogenase type 2 protects the mineralocorticoid receptor from activation by glucocorticoids; however, high glucocorticoid concentrations and absent 11β-hydroxysteroid dehydrogenase type 2 in some tissues make glucocorticoids highly relevant mineralocorticoid receptor ligands. We investigated the effects of corticosterone (10 −6 to 10 −12 mol/L) on early vascular mineralocorticoid receptor signaling by Western blotting, confocal microscopy, and myography. Corticosterone initiated extracellular signal–regulated kinase 1/2 phosphorylation in rat vascular smooth muscle cells at ≥10 −11 mol/L doses. Protein synthesis inhibitors had no effect, indicating a nongenomic action. Corticosterone also stimulated c-Jun N-terminal kinase, p38, Src, and Akt phosphorylation at 15 minutes and enhanced angiotensin II–induced signaling at 5 minutes. A specific epidermal growth factor receptor blocker, AG1478, as well as the Src inhibitor PP2, markedly reduced corticosterone-induced extracellular signal–regulated kinase 1/2 phosphorylation, as did preincubation of cells with the mineralocorticoid receptor antagonist spironolactone. Silencing mineralocorticoid receptor with small interfering RNA abolished corticosterone-induced effects. Corticosterone (10 −9 mol/L) enhanced phenylephrine-induced contraction of intact aortic rings. These effects were dependent on the intact endothelium, mineralocorticoid receptor, and mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase signaling. We conclude that corticosterone induces rapid mineralocorticoid receptor signaling in vascular smooth muscle cells that involves mitogen-activated protein kinase kinase/extracellular signal–regulated kinase–dependent pathways. These new mineralocorticoid receptor–dependent signaling pathways suggest that glucocorticoids may contribute to vascular disease via mineralocorticoid receptor signaling, independent of circulating aldosterone.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.107.105718
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 2094210-2
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  • 6
    Online Resource
    Online Resource
    A Peroxisome Proliferator-Activated Receptor-α Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury
    Elsevier BV ; 2004
    In:  The American Journal of Pathology Vol. 164, No. 2 ( 2004-02), p. 521-532
    Details
    In: The American Journal of Pathology, Elsevier BV, Vol. 164, No. 2 ( 2004-02), p. 521-532
    Type of Medium: Online Resource
    ISSN: 0002-9440
    URL: Article
    DOI: 10.1016/S0002-9440(10)63142-2
    RVK:
    XA 10000
    RVK:
    XA 19800
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
    detail.hit.zdb_id: 1480207-7
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  • 7
    Online Resource
    Online Resource
    Dehydroepiandrosterone-Induced Phosphorylation and Translocation of FoxO1 Depend on the Mineralocorticoid Receptor
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Hypertension Vol. 58, No. 3 ( 2011-09), p. 471-478
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 58, No. 3 ( 2011-09), p. 471-478
    Abstract: In humans, dehydroepiandrosterone (DHEA), with its sulfate, is the most abundant adrenal steroid, whereas the rat adrenals are not capable of synthesizing this steroid. Circulating concentrations of DHEA sulfate lie in the millimolar range and those of DHEA in the subnanomolar range. DHEA exerts protective potential during vascular remodeling, although the underlying mechanisms of this protection are imperfectly defined. We hypothesized that physiological doses of DHEA alter signaling pathways that are of central importance for vascular integrity. We exposed human endothelial cells, vascular smooth muscle cells, and fibroblasts to DHEA (10 −6 to 10 −10 mol/L) and observed a dose- and time-dependent increase of extracellular signal-regulated kinases 1 and 2 activation. Similar results were observed in rat vascular smooth muscle cells. In addition, in rat vascular smooth muscle cells, we found altered phosphorylation and cellular translocation of the transcription factor FoxO1. Pharmacological blockade of the mineralocorticoid receptor (MR) with eplerenone or small interfering RNA-mediated MR-silencing prevented DHEA-induced extracellular signal-regulated kinase 1/2 phosphorylation and its effects on FoxO1. Of note, in a cell-based MR transactivation assay, we did not find any agonist effect of DHEA on MR activity. We conclude that DHEA induces early signaling events in vascular cells that might underlie the DHEA-mediated protection against vasculopathies. These effects are dependent on the MR, although the finding that DHEA fails to act as a direct MR agonist suggests that additional signaling proteins are involved. In this regard, DHEA may either interact with coeffectors to modify MR activity or serves as a ligand for a yet unknown receptor that might transactivate the MR.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.111.171280
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
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  • 8
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    Online Resource
    Aldosterone Modulates Endothelial Permeability and Endothelial Nitric Oxide Synthase Activity by Rearrangement of the Actin Cytoskeleton
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 61, No. 2 ( 2013-02), p. 501-508
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 61, No. 2 ( 2013-02), p. 501-508
    Abstract: Aldosterone (Aldo) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Aldo alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells were exposed to Aldo (10 –9 mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions and activation of intracellular signaling pathways were determined. Aldo increased endothelial permeability for molecules ≤70 kDa within 60 minutes. A transient loss of cortical actin with formation of actin stress fibers and disruption of continuous adherens and tight junction strands accompanied these changes. Mineralocorticoid receptor blockade, inhibition of RhoA, or disruption of extracellular-regulated protein kinase1/2 signaling pathways attenuated the Aldo-related effects. Moreover, Aldo-induced cytoskeletal rearrangement led to rapid dephosphorylation of protein kinase B and subsequent deactivation of endothelial nitric oxide synthase. Ex vivo tracer flux experiments with Evans blue–conjugated albumin demonstrated a concordant response to Aldo in freshly isolated umbilical arteries. Furthermore, low-dose cortisol (3×10 –10 to 3×10 –9 mol/L) mimics the effect of Aldo on endothelial integrity, and Aldo, by upregulating11β-hydroxysteroid dehydrogenase type 2, might even aggravate this deleterious effect of low-dose cortisol. We suggest that these mechanisms may contribute to the vasculopathy induced by inappropriate mineralocorticoid receptor activation.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.111.196832
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
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