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  • 1
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    Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Renal Physiology Vol. 303, No. 12 ( 2012-12-15), p. F1601-F1607
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 303, No. 12 ( 2012-12-15), p. F1601-F1607
    Abstract: Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH 4 ) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH 4 to dihydrobiopterin (BH 2 ); the BH 4 -to-BH 2 ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47 phox , and p67 phox was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00449.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477287-5
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  • 2
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    Essential Role of Endothelial Nitric Oxide Synthase in Vascular Effects of Erythropoietin
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Hypertension Vol. 49, No. 5 ( 2007-05), p. 1142-1148
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 49, No. 5 ( 2007-05), p. 1142-1148
    Abstract: Erythropoietin (EPO) fosters tissue oxygenation by stimulating erythropoiesis. More recently, EPO has been recognized as a tissue-protective cytokine. In this study, we tested the hypothesis that endothelial NO synthase (eNOS) plays a key role in the vascular protective effect of EPO. A murine model of wire-induced injury of carotid artery was used to examine the effect of EPO on endothelial repair and arterial wall architecture. Recombinant human EPO (1000 U/kg, SC, biweekly) was administered for 2 weeks in wild-type and eNOS-deficient mice after which reactivity of isolated carotid arteries was studied in vitro, and the vasculature was histologically assessed. Injured arteries exhibited impairment of endothelium-dependent relaxations to acetylcholine ( P 〈 0.05). This was associated with increased medial cross-sectional area ( P 〈 0.05). EPO upregulated expression of phosphorylated Ser1177-eNOS and normalized the vasodilator response to acetylcholine ( P 〈 0.05). Furthermore, EPO prevented the injury-induced increase in medial cross-sectional area ( P 〈 0.05). The vascular protective effects of EPO were abolished in eNOS-deficient mice. Most notably, EPO significantly increased systolic blood pressure and enhanced medial thickening of injured carotid arteries in eNOS-deficient mice ( P 〈 0.05). Our results demonstrate that EPO prevents aberrant remodeling of the injured carotid artery. The protective effects of EPO are critically dependent on activation of eNOS.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.106.085704
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 2094210-2
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  • 3
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    Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries
    SAGE Publications ; 2018
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 38, No. 10 ( 2018-10), p. 1715-1726
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 38, No. 10 ( 2018-10), p. 1715-1726
    Abstract: The exact physiological function of amyloid-β precursor protein (APP) in endothelial cells is unknown. Endothelium-specific APP-deficient (eAPP −/− ) mice were created to gain new insights into the role of APP in the control of vascular endothelial function. Endothelium-dependent relaxations to acetylcholine were significantly impaired in basilar arteries of global APP knockout (APP −/− ) and eAPP −/− mice ( P  〈  0.05). In contrast, endothelium-independent relaxations to nitric oxide (NO)-donor diethylamine-NONOate were unchanged. Western blot analysis revealed that protein expression of endothelial nitric oxide synthase (eNOS) was significantly downregulated in large cerebral arteries of APP −/− mice and eAPP −/− mice as compared to respective wild-type littermates ( P  〈  0.05). Furthermore, basal levels of cyclic guanosine monophosphate (cGMP) were also significantly reduced in large cerebral arteries of APP-deficient mice ( P  〈  0.05). In contrast, protein expression of prostacyclin synthase as well as levels of cyclic adenosine monophosphate (cAMP) was not affected by genetic inactivation of APP in endothelial cells. By using siRNA to knockdown APP in cultured human brain microvascular endothelial cells we also found a significant downregulation of eNOS mRNA and protein expressions in APP-deficient endothelium ( P  〈  0.05). These findings indicate that under physiological conditions, expression of APP in cerebral vascular endothelium plays an important protective function by maintaining constitutive expression of eNOS .
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1177/0271678X17735418
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2039456-1
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  • 4
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    Abstract 1493: Erythropoietin Stimulates Endothelial Biosynthesis of Tetrahydrobiopterin by Activation of Phosphatidylinositol 3-kinase/Protein Kinase B Signal Transduction Pathway
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Vol. 116, No. suppl_16 ( 2007-10-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
    Abstract: Erythropoietin (EPO) has been recognized as a tissue protective cytokine. Recently, it has been shown that vascular protective effects of EPO are dependent on activation of endothelial nitric oxide synthase (eNOS). Tetrahydrobiopterin (BH 4 ) is an essential cofactor required for enzymatic activity of eNOS. Therefore, our objective was to characterize the effect of EPO on biosynthesis of BH 4 in vascular wall. Incubation of isolated wild-type (C57BL/6J) mouse aortas for 18 hours at 37°C in minimal essential medium supplemented with recombinant human EPO (1–50 U/ml) caused concentration-dependent increase in intracellular levels of BH 4 as determined by HPLC analysis. Maximum biosynthesis of BH 4 was detected at therapeutic concentrations of 5 U/mL (15.8±1.3 pmol/mg protein; P 〈 0.05 vs control: 8.2±0.4 pmol/mg protein; n=6 – 8). Oxidative products of BH 4 , 7,8-dihydrobiopterin, were unaffected by EPO indicating that EPO does not affect oxidation of BH 4 . Removal of the endothelium abolished EPO-induced biosynthesis of BH 4 (P 〈 0.05; n=5) demonstrating that the vascular endothelium is a major source of BH 4 . Treatment of intact isolated wild-type mouse aortas with a selective phosphatidylinositol (PI)3-kinase inhibitor wortmannin (1 μM) significantly reduced BH 4 biosynthesis by EPO (8.4±0.6 pmol/mg protein; P 〈 0.05; n=6). Stimulatory effect of EPO on production of BH 4 in aorta was also detected in wild-type mice treated with recombinant human EPO (1000 U/kg, s.c. biweekly) for 14 days (P 〈 0.05; n=6). This vascular effect was abolished in protein kinase B (Akt) 1-deficient mice treated with EPO (P 〈 0.05; n=5). Furthermore, aortic GTP cyclohydrolase I (GTPCH I) enzymatic activity was augmented in EPO treated wild-type mice (0.48±0.12 pmol neopterin/mg protein; P 〈 0.05 vs control: 0.23±0.05 pmol neopterin/mg; n=4) but not in EPO treated Akt 1-deficient mice (0.21±0.03 pmol neopterin/mg; n=4), indicating that the selective increase in BH 4 levels was caused by de-novo biosynthesis of BH 4 via Akt/GTPCH I pathway. Our results demonstrate that EPO stimulates biosynthesis of BH 4 in vascular endothelium. This effect is most likely designed to provide optimal intracellular concentration of cofactor necessary for EPO-induced elevation of eNOS activity.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.116.suppl_16.II_308
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1466401-X
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  • 5
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    Obesity Is Associated With Tissue-Specific Activation of Renal Angiotensin-Converting Enzyme In Vivo : Evidence for a Regulatory Role of Endothelin
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Hypertension Vol. 35, No. 1 ( 2000-01), p. 329-336
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 1 ( 2000-01), p. 329-336
    Abstract: Abstract —In the C57BL/6J mice model, we investigated whether obesity affects the function or expression of components of the tissue renin-angiotensin system and whether endothelin (ET)-1 contributes to these changes. ACE activity (nmol · L His-Leu · mg protein −1 ) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252 , an orally active ET A receptor antagonist. ACE mRNA expression was measured in the kidney, and the effects of LU135252 on purified human ACE were determined. Aortic and renal tissue ET-1 protein content was measured, and the vascular contractility to angiotensin II was assessed. Obesity was associated with a tissue-specific increase in ACE activity in the kidney (55±4 versus 33±3 nmol/L) but not in the lung (34±2 versus 32±2 nmol/L). Long-term LU135252 treatment completely prevented this activation (13.3±0.3 versus 55±4 nmol/L, P 〈 0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity. Obesity potentiated contractions in response to angiotensin II in the aorta (from 6±2% to 33±5% KCl) but not in the carotid artery (4±1% to 3.6±1% KCl), an effect that was completely prevented with LU135252 treatment (6±0.4% versus 33±5% KCl). No effect of LU135252 on purified ACE was observed. Thus, obesity is associated with the activation of renal ACE in vivo independent of its mRNA expression and enhanced vascular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonists may exert organ protection.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/01.HYP.35.1.329
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
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  • 6
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    Effect of Chronic Nitric Oxide Deficiency on Angiotensin II–Induced Hypertrophy of Rat Basilar Artery
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Stroke Vol. 29, No. 5 ( 1998-05), p. 1031-1036
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 5 ( 1998-05), p. 1031-1036
    Abstract: Background and Purpose —Although in vitro studies suggest that nitric oxide has an inhibitory effect on cellular proliferation and migration, in vivo experiments failed to support this conclusion. The present study was designed to determine the effect of endogenous nitric oxide on angiotensin II–induced hypertrophy of small arteries in vivo. Methods —Angiotensin II (200 ng/kg per minute), alone or in combination with N ω -nitro- l -arginine methyl ester (L-NAME) (60 mg/kg per day), was administered for 2 weeks in normotensive rats. Basilar arteries were harvested, and their geometry was determined in perfused and pressurized conditions. Results —Angiotensin II increased media thickness, media-lumen ratio, and cross-sectional area of the arteries, confirming the presence of hypertrophic remodeling. The concomitant administration of L-NAME, an inhibitor of nitric oxide synthesis, prevented vascular hypertrophy. The remodeling of the basilar artery geometry in the combined treatment was of eutrophic nature, similar to that observed with the administration of L-NAME alone. Conclusions —Our results suggest that endogenous nitric oxide does not inhibit angiotensin II–induced vascular hypertrophy in vivo. Nitric oxide may even be a necessary factor for hypertrophy to develop.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/01.STR.29.5.1031
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1998
    detail.hit.zdb_id: 1467823-8
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  • 7
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    Mechanism of Endothelial Dysfunction in Apolipoprotein E–Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 21, No. 6 ( 2001-06), p. 1017-1022
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 21, No. 6 ( 2001-06), p. 1017-1022
    Abstract: Abstract —Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10 − 9 to 10 − 5 mol/L) and Ca 2+ ionophore (10 − 9 to 10 − 6 mol/L) and endothelium-independent relaxations to diethylammonium ( Z )-1-( N , N -diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10 − 10 to 10 − 5 mol/L) compared with aortic rings from C57BL/6J mice ( P 〈 0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O 2 − ) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn–superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10 − 5 mol/L), reduced O 2 − production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice ( P 〈 0.05). [ 14 C] l -Citrulline assay showed a decrease of Ca 2+ -dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice ( P 〈 0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice ( P 〈 0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O 2 − and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O 2 − and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.21.6.1017
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
    detail.hit.zdb_id: 1494427-3
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  • 8
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    Effects of Chronic ET A -Receptor Blockade in Angiotensin II-Induced Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Hypertension Vol. 29, No. 1 ( 1997-01), p. 435-441
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 1 ( 1997-01), p. 435-441
    Abstract: Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252 , on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35±5 mm Hg; tail-cuff method) compared with placebo ( P 〈 .05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase ( P 〈 .05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group ( P 〈 .05 versus placebo) and improved by concomitant chronic LU135252 treatment ( P 〈 .05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine ( r =−.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment ( P 〈 .05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 ( P 〈 .05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 ( P 〈 .05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/01.HYP.29.1.435
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 2094210-2
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  • 9
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    Abstract P274: Endothelial Dysfunction of Conduit Arteries in Amyloid Precursor Protein-Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hypertension Vol. 72, No. Suppl_1 ( 2018-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 72, No. Suppl_1 ( 2018-09)
    Abstract: Amyloid precursor protein (APP) is an integral membrane protein expressed in the peripheral arteries. However, the exact vascular physiological function of APP is unknown. Male APP-deficient (APP –/– ) and their wild-type littermates (WT) mice were used to characterize the phenotype of APP in the control of vascular function. Isometric force of isolated aortic rings was recorded in organ chambers. Circulating levels of norepinephrine and epinephrine were significantly enhanced in APP –/– mice (4723±566 pg/mL and 854±98 pg/mL, respectively P 〈 0.05 vs. WT: 1999±319 pg/mL and 429±71 pg/mL, respectively; n=13). The efficacy of phenylephrine induced contractions were significantly reduced in the aorta of APP –/– mice (21±3%, P 〈 0.05 vs. WT: 47±4%; n=10) while contractions to prostaglandin F 2α were unchanged (135±4%, P=n.s. vs. WT: 133±3%; n=9). Western blot analysis revealed that protein expression of alpha1D adrenergic receptors was significantly downregulated in APP –/– mice aortas (0.21±0.05 O.D.; P 〈 0.05 vs. WT: 0.48±0.11 O.D.; n=6). In contrast, endothelium-dependent relaxations to β-agonist isoproterenol were significantly enhanced in APP –/– mice aortas (P 〈 0.05; n=10) while endothelium-dependent relaxations to acetylcholine were unaltered (P=n.s.; n=12). Incubation of aortic rings with indomethacin significantly impaired relaxations to isoproterenol as well as acetylcholine in APP –/– mice (P 〈 0.05; n=8) while concomitant treatment with NOS inhibitor L-NAME completely abolished relaxations to both agonists (P 〈 0.05; n=6-7). Incubation of aortic rings with isoproterenol significantly increased cAMP in the aortas of APP –/– mice (16.2±4.1 pmol/mg; P 〈 0.05 vs. WT: 6.6±4.1 pmol/mg; n=7). Furthermore, cAMP levels were significantly enhanced by acetylcholine in APP –/– mice aortas (38±9 pmol/mg; P 〈 0.05 vs. WT: 14±3 pmol/mg; n=8) while acetylcholine stimulated cGMP levels were reduced (59±5 pmol/mg; P 〈 0.05 vs. WT: 83±7 pmol/mg; n=12). Our results suggest that increased circulating levels of catecholamines in APP –/– mice are responsible for observed vascular phenotype. These findings indicate that under physiological conditions, APP expression plays an important role in control of vascular endothelial function .
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.72.suppl_1.P274
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 10
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    Erythropoietin Increases Endothelial Biosynthesis of Tetrahydrobiopterin by Activation of Protein Kinase Bα/Akt1
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Hypertension Vol. 52, No. 1 ( 2008-07), p. 93-99
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 1 ( 2008-07), p. 93-99
    Abstract: Tetrahydrobiopterin (BH 4 ) is an essential cofactor required for enzymatic activity of endothelial NO synthase. Recently, it has been shown that vascular protective effects of erythropoietin (EPO) are dependent on activation of endothelial NO synthase. Therefore, our objective was to characterize the effect of EPO on the biosynthesis of BH 4 in the vascular wall. Incubation of isolated C57BL/6J mouse aortas for 18 hours with recombinant human EPO (1 to 50 U/mL) caused a concentration-dependent increase in intracellular BH 4 levels and activity of GTP-cyclohydrolase I. Maximal biosynthesis of BH 4 was detected at therapeutic concentrations of 5 U/mL. Removal of the endothelium abolished EPO-induced biosynthesis of BH 4 demonstrating that the vascular endothelium is a major source of BH 4 . Treatment with a selective phosphatidylinositol 3-kinase inhibitor wortmannin significantly reduced BH 4 biosynthesis stimulated by EPO. The stimulatory effect of EPO on vascular GTP-cyclohydrolase I activity, BH 4 production, and phosphorylation of endothelial NO synthase was also detected in vivo in mice treated with recombinant human EPO. These effects of EPO were abolished in protein kinase Bα/Akt1-deficient mice. In addition, EPO significantly increased systolic blood pressure and the number of circulating platelets in Akt1-deficient mice. Our results demonstrate that EPO stimulates biosynthesis of BH 4 in vascular endothelium and that the increase in BH 4 levels is caused by de novo biosynthesis of BH 4 via the phosphatidylinositol 3-kinase/Akt1 pathway. This effect is most likely designed to provide optimal intracellular concentration of the cofactor necessary for EPO-induced elevation of endothelial NO synthase activity.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.108.114041
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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