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Toward Precision Medicine in Pulmonary Arterial Hypertension.
Austin ED, Loyd JE
(2015) Am J Respir Crit Care Med 192: 1272-4
MeSH Terms: Antihypertensive Agents, Endothelin Receptor Antagonists, Endothelin-1, Female, Humans, Hypertension, Pulmonary, Male, Polymorphism, Single Nucleotide
Added February 21, 2017
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8 MeSH Terms
Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium.
Li Q, Park K, Li C, Rask-Madsen C, Mima A, Qi W, Mizutani K, Huang P, King GL
(2013) Circ Res 113: 418-27
MeSH Terms: Animals, Aorta, Apolipoproteins E, Atherosclerosis, Disease Models, Animal, Endothelin-1, Endothelium, Vascular, Female, Insulin Resistance, Isoenzymes, Male, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Protein Kinase C beta, Proto-Oncogene Proteins c-akt, Up-Regulation, Vascular Cell Adhesion Molecule-1
Show Abstract · Added July 21, 2014
RATIONALE - Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.
OBJECTIVE - To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.
METHODS AND RESULTS - Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix.
CONCLUSIONS - Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.
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18 MeSH Terms
Chronic endothelin-1 infusion elevates glomerular sieving coefficient and proximal tubular albumin reuptake in the rat.
Saleh MA, Sandoval RM, Rhodes GJ, Campos-Bilderback SB, Molitoris BA, Pollock DM
(2012) Life Sci 91: 634-7
MeSH Terms: Animals, Bowman Capsule, Endothelin-1, Kidney Glomerulus, Kidney Tubules, Proximal, Male, Microscopy, Fluorescence, Multiphoton, Permeability, Rats, Rats, Wistar, Serum Albumin, Time Factors
Show Abstract · Added July 31, 2014
AIM - We have previously found that chronic endothelin-1 (ET-1) infusion in Sprague-Dawley rats increases glomerular permeability to albumin (P(alb)) as assessed in vitro independent of blood pressure with no observed albuminuria. In this study, we hypothesized that ET-1 increases glomerular albumin filtration with accompanied increase in albumin uptake via the proximal tubule, which masks the expected increase in urinary albumin excretion.
MAIN METHODS - Nonfasting Munich-Wistar Fromter rats were surgically prepared for in vivo imaging (n=6). Rats were placed on the microscope stage with the exposed kidney placed in a cover slip-bottomed dish bathed in warm isotonic saline. Rats were then injected i.v. with rat serum albumin conjugated to Texas Red that was observed to enter capillary loops of superficial glomeruli, move into Bowman's space, bind to the proximal tubular cell brush border and reabsorbed across the apical membrane. Glomerular sieving coefficient (GSC) was calculated as the ratio of conjugated albumin within the glomerular capillary versus that in Bowman's space. Rats were again studied after 2 weeks of chronic ET-1 (2 pmol/kg/min; i.v. osmotic minipump).
KEY FINDINGS - Glomerular sieving coefficient was significantly increased in rats following chronic ET-1 infusion (0.025 ± 0.005 vs. 0.017 ± 0.003, p<0.05). Mean fluorescence intensity for conjugated albumin within proximal tubules was increased by ET-1 infusion: 118.40 ± 6.34 vs. 74.27 ± 4.45 pixel intensity (p<0.01).
SIGNIFICANCE - These data provide in vivo evidence that ET-1 directly increases glomerular permeability to albumin and that albuminuria is prevented by increased PT albumin uptake in the rat.
Copyright © 2012 Elsevier Inc. All rights reserved.
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12 MeSH Terms
Endothelin in renal inflammation and hypertension.
Saleh MA, Pollock DM
(2011) Contrib Nephrol 172: 160-170
MeSH Terms: Animals, Diabetic Nephropathies, Endothelin-1, Humans, Hypertension, Nephritis, Receptors, Endothelin
Show Abstract · Added July 31, 2014
Over the years, a very large amount of evidence has accumulated indicating that endothelin (ET)-1 is an important stimulus for inflammation. This is true for a wide range of organ system diseases, including chronic kidney disease. Nonetheless, our understanding of the role and mechanisms by which ET-1 promotes the activation of both the innate and adaptive immune systems is not understood. ET-1 can directly activate neutrophils as well as endothelial cells to stimulate production of chemoattractant factors, such as monocyte chemoattractant factor-1, and increase synthesis of cell adhesion molecules, such as soluble ICAM-1. The mechanisms that trigger these events, however, are less clear. Elevated blood pressure as well as hyperglycemia could be important factors that facilitate ET-1-dependent inflammation. While renal inflammation has not been used as an endpoint for drug development, the rationale for the use of ET antagonists as anti-inflammatory agents in chronic kidney disease is quite strong, based on animal studies and at least one study in humans with nondiabetic nephritis. While the preponderance of evidence suggests that ET(A) selective antagonists are advantageous over combined ET(A/B) receptor blockers, considerably more work needs to be done in order to understand the complex role of ET in renal inflammation.
Copyright © 2011 S. Karger AG, Basel.
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7 MeSH Terms
Endothelin-1 increases glomerular permeability and inflammation independent of blood pressure in the rat.
Saleh MA, Boesen EI, Pollock JS, Savin VJ, Pollock DM
(2010) Hypertension 56: 942-9
MeSH Terms: Analysis of Variance, Animals, Atrasentan, Blood Pressure, Endothelin Receptor Antagonists, Endothelin-1, Immunoassay, Immunohistochemistry, Inflammation, Kidney Glomerulus, Male, Permeability, Pyrrolidines, Rats, Rats, Sprague-Dawley, Receptors, Endothelin
Show Abstract · Added July 31, 2014
Endothelin (ET) 1 is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nmol/L) significantly increased glomerular permeability to albumin, reaching a maximum after 4 hours. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased glomerular permeability to albumin and nephrin excretion rate, effects that were attenuated in rats given an ET(A) receptor antagonist (ABT-627, 5 mg/kg per day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1-infused rats with the selective ET(A) antagonist significantly reduced glomerular permeability to albumin, an effect not observed with acute treatment with a selective ET(B) antagonist. Chronic ET-1 infusion increased glomerular and plasma soluble intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3-positive staining, respectively). These effects were all attenuated in rats given an ET(A) selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ET(A) receptor activation independent of changes in arterial pressure.
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16 MeSH Terms
BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension.
Talati M, West J, Blackwell TR, Loyd JE, Meyrick B
(2010) Am J Physiol Lung Cell Mol Physiol 299: L363-73
MeSH Terms: Adolescent, Adult, Aged, Animals, Aspartic Acid Endopeptidases, Bone Morphogenetic Protein Receptors, Type II, Endothelin-1, Endothelin-Converting Enzymes, Female, Gene Expression, Humans, Hypertension, Pulmonary, Macrophages, Macrophages, Alveolar, Male, Metalloendopeptidases, Mice, Mice, Mutant Strains, Microscopy, Confocal, Middle Aged, Mutation, Receptor, Endothelin A, Receptor, Endothelin B, Tissue Distribution, Young Adult
Show Abstract · Added March 5, 2014
Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.
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25 MeSH Terms
Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation.
Zhou Y, Hagood JS, Lu B, Merryman WD, Murphy-Ullrich JE
(2010) J Biol Chem 285: 22382-93
MeSH Terms: Amino Acid Motifs, Animals, Cell Differentiation, Cell Membrane, Cell-Free System, Endothelin-1, Fibroblasts, Humans, Immobilized Proteins, Lung, Mice, Muscle Contraction, Myoblasts, Oxazoles, Protein Binding, Rats, Receptors, Vitronectin, Solubility, Thy-1 Antigens, Transforming Growth Factor beta1
Show Abstract · Added February 12, 2015
Myofibroblasts, key effector cells in tissue fibrosis, are specialized contractile cells. Lung myofibroblast contraction induces integrin alpha(v)beta(5)-dependent latent transforming growth factor (TGF)-beta1 activation suggests that myofibroblast contractility may be a driving force for the persistent myofibroblast differentiation observed in fibrotic lungs. Understanding the mechanisms that regulate fibroblast contraction and mechanotransduction will add new insights into the pathogenesis of lung fibrosis and may lead to new therapeutic approaches for treating fibrotic lung diseases. We and others previously demonstrated that lung fibroblast expression of Thy-1 prevents lung fibrosis. The mechanisms underlying the anti-fibrotic effect of Thy-1 are not well understood. In this study, we showed that Thy-1 interacts with integrin alpha(v)beta(5), both in a cell-free system and on the cell surface of rat lung fibroblasts. Thy-1-integrin alpha(v)beta(5) interactions are RLD-dependent because mutated Thy-1, in which RLD is replaced by RLE, loses the ability to bind the integrin. Furthermore, Thy-1 expression prevents fibroblast contraction-induced, integrin alpha(v)beta(5)-dependent latent TGF-beta1 activation and TGF-beta1-dependent lung myofibroblast differentiation. In contrast, lack of Thy-1 expression or disruption of Thy-1-alpha(v)beta(5) interactions renders lung fibroblasts susceptible to contraction-induced latent TGF-beta1 activation and myofibroblast differentiation. These data suggest that Thy-1-integrin alpha(v)beta(5) interactions inhibit contraction-induced latent TGF-beta1 activation, presumably by blocking the binding of extracellular matrix-bound latent TGF-beta1 with integrin alpha(v)beta(5). Our studies suggest that targeting key mechanotransducers to inhibit mechanotransduction might be an effective approach to inhibit the deleterious effects of myofibroblast contraction on lung fibrogenesis.
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20 MeSH Terms
Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep.
Volk KA, Roghair RD, Jung F, Scholz TD, Lamb FS, Segar JL
(2010) Am J Physiol Regul Integr Comp Physiol 298: R1607-14
MeSH Terms: Animals, Catalase, Coronary Vessels, Dexamethasone, Endothelin-1, Endothelium, Female, Fetus, Glucocorticoids, Muscle, Smooth, Vascular, Nitric Oxide, Nitric Oxide Synthase Type III, Pregnancy, Sheep, Superoxide Dismutase, Vasoconstriction
Show Abstract · Added February 22, 2016
Exposure of the early-gestation ovine fetus to exogenous glucocorticoids induces changes in postnatal cardiovascular physiology. We sought to characterize coronary artery vascular function in this model by elucidating the contribution of nitric oxide and reactive oxygen species to altered coronary vascular reactivity and examining the proliferative potential of coronary artery vascular smooth muscle cells. Dexamethasone (dex, 0.28 mg x kg(-1) x day(-1) for 48 h) was administered to pregnant ewes at 27-28-day gestation (term 145 days). Coronary arteries were isolated from 1- to 2-wk-old dex-exposed offspring and aged-matched controls. Compared with controls, coronary arteries from dex-exposed lambs demonstrated enhanced vasoconstriction to endothelin-1 and ACh that was abolished by endothelial removal or preincubation with the nitric oxide synthase inhibitor L-NNA, membrane-permeable superoxide dismutase + catalase, or apamin + charybdotoxin, but not indomethacin. The rate of coronary vascular smooth muscle cell (VSMC) proliferation was also significantly greater in dex-exposed lambs. Protein levels of the proliferating cell nuclear antigen were increased and alpha-smooth muscle actin decreased in dex-exposed coronary VSMC, consistent with a proliferative state. Finally, expression of the NADPH oxidase Nox 4, but not Nox 1, mRNA was also decreased in coronary VSMC from dex-exposed lambs. These findings suggest an important interaction exists between early-gestation glucocorticoid exposure and reactive oxygen species that is associated with alterations in endothelial function and coronary VSMC proliferation. These changes in coronary physiology are consistent with those associated with the development of atherosclerosis and may provide an important link between an adverse intrauterine environment and increased risk for coronary artery disease.
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16 MeSH Terms
O-GlcNAcylation contributes to augmented vascular reactivity induced by endothelin 1.
Lima VV, Giachini FR, Carneiro FS, Carneiro ZN, Saleh MA, Pollock DM, Fortes ZB, Carvalho MH, Ergul A, Webb RC, Tostes RC
(2010) Hypertension 55: 180-8
MeSH Terms: Acetylglucosamine, Animals, Aorta, Thoracic, Atrasentan, Blood Pressure, Blotting, Western, Desoxycorticosterone, Drug Synergism, Endothelin-1, Glycoproteins, Glycosylation, Hypertension, In Vitro Techniques, Male, N-Acetylglucosaminyltransferases, Phenylephrine, Pyrrolidines, Rats, Rats, Wistar, Time Factors, Vasoconstriction, Vasoconstrictor Agents
Show Abstract · Added July 31, 2014
O-GlcNAcylation augments vascular contractile responses, and O-GlcNAc-proteins are increased in the vasculature of deoxycorticosterone-acetate salt rats. Because endothelin 1 (ET-1) plays a major role in vascular dysfunction associated with salt-sensitive forms of hypertension, we hypothesized that ET-1-induced changes in vascular contractile responses are mediated by O-GlcNAc modification of proteins. Incubation of rat aortas with ET-1 (0.1 mumol/L) produced a time-dependent increase in O-GlcNAc levels and decreased expression of O-GlcNAc transferase and beta-N-acetylglucosaminidase, key enzymes in the O-GlcNAcylation process. Overnight treatment of aortas with ET-1 increased phenylephrine vasoconstriction (maximal effect [in moles]: 19+/-5 versus 11+/-2 vehicle). ET-1 effects were not observed when vessels were previously instilled with anti-O-GlcNAc transferase antibody or after incubation with an O-GlcNAc transferase inhibitor (3-[2-adamantanylethyl]-2-[{4-chlorophenyl}azamethylene]-4-oxo-1,3-thiazaperhyd roine-6-carboxylic acid; 100 mumol/L). Aortas from deoxycorticosterone-acetate salt rats, which exhibit increased prepro-ET-1, displayed increased contractions to phenylephrine and augmented levels of O-GlcNAc proteins. Treatment of deoxycorticosterone-acetate salt rats with an endothelin A antagonist abrogated augmented vascular levels of O-GlcNAc and prevented increased phenylephrine vasoconstriction. Aortas from rats chronically infused with low doses of ET-1 (2 pmol/kg per minute) exhibited increased O-GlcNAc proteins and enhanced phenylephrine responses (maximal effect [in moles]: 18+/-2 versus 10+/-3 control). These changes are similar to those induced by O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate, an inhibitor of beta-N-acetylglucosaminidase. Systolic blood pressure (in millimeters of mercury) was similar between control and ET-1-infused rats (117+/-3 versus 123+/-4 mm Hg; respectively). We conclude that ET-1 indeed augments O-GlcNAc levels and that this modification contributes to the vascular changes induced by this peptide. Increased vascular O-GlcNAcylation by ET-1 may represent a mechanism for hypertension-associated vascular dysfunction or other pathological conditions associated with increased levels of ET-1.
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22 MeSH Terms
Endogenous aldosterone contributes to acute angiotensin II-stimulated plasminogen activator inhibitor-1 and preproendothelin-1 expression in heart but not aorta.
Luther JM, Wang Z, Ma J, Makhanova N, Kim HS, Brown NJ
(2009) Endocrinology 150: 2229-36
MeSH Terms: Aldosterone, Angiotensin II, Animals, Aorta, Blood Pressure, Cytochrome P-450 CYP11B2, Drug Interactions, Endothelin-1, Heart, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium, Plasminogen Activator Inhibitor 1, Receptor, Angiotensin, Type 1, Time Factors, Up-Regulation
Show Abstract · Added December 10, 2013
To test the hypothesis that angiotensin (Ang) II induces profibrotic gene expression through endogenous aldosterone, we measured the effect of 4 h infusion (600 ng/kg x min) of Ang II on tissue mRNA expression of plasminogen activator inhibitor 1 (PAI-1), preproendothelin-1 (ppET-1), TGF-beta, and osteopontin in wild-type (WT), aldosterone synthase-deficient (AS(-/-)), and AS(-/-) mice treated with aldosterone (either 500 ng/d for 7 d or 250 ng as a concurrent 4 h infusion). Ang II increased aldosterone in WT (P < 0.001) but not in AS(-/-) mice. Aldosterone (7 d) normalized basal aldosterone concentrations in AS(-/-) mice; however, there was no further effect of Ang II on aldosterone (P = NS). Basal cardiac and aortic PAI-1 and ppET-1 expression were similar in WT and AS(-/-) mice. Ang II-stimulated PAI-1 (P < 0.001) and ppET-1 expression (P = 0.01) was diminished in the heart of AS(-/-) mice; treatment with aldosterone for 4 h or 7 d restored PAI-1 and ppET-1 mRNA responsiveness to Ang II in the heart. Ang II increased PAI-1 (P = 0.01) expression in the aorta of AS(-/-) as well as WT mice. In the kidney, basal PAI-1, ppET-1, and TGF-beta mRNA expression was increased in AS(-/-) compared with WT mice and correlated with plasma renin activity. Ang II did not stimulate osteopontin or TGF-beta expression in the heart or kidney. Endogenous aldosterone contributes to the acute stimulatory effect of Ang II on PAI-1 and ppET-1 mRNA expression in the heart; renin activity correlates with basal profibrotic gene expression in the kidney.
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17 MeSH Terms