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Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension.
Nozik-Grayck E, Woods C, Taylor JM, Benninger RK, Johnson RD, Villegas LR, Stenmark KR, Harrison DG, Majka SM, Irwin D, Farrow KN
(2014) Am J Physiol Lung Cell Mol Physiol 307: L868-76
MeSH Terms: Animals, Blood Pressure, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 5, Estrogen Antagonists, GTP Cyclohydrolase, Guanylate Cyclase, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Lung, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Pulmonary Artery, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Soluble Guanylyl Cyclase, Superoxide Dismutase, Tamoxifen
Show Abstract · Added March 31, 2015
Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SOD(loxp/loxp) × Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function.
Copyright © 2014 the American Physiological Society.
1 Communities
2 Members
0 Resources
20 MeSH Terms
Opposing regulation of human alveolar type II cell differentiation by nitric oxide and hyperoxia.
Johnston LC, Gonzales LW, Lightfoot RT, Guttentag SH, Ischiropoulos H
(2010) Pediatr Res 67: 521-5
MeSH Terms: Alveolar Epithelial Cells, Biomarkers, Cell Differentiation, Cell Hypoxia, Cells, Cultured, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 5, Gene Expression Regulation, Gestational Age, Guanylate Cyclase, Humans, Nitric Oxide, Nuclear Proteins, Oxygen, Pulmonary Surfactant-Associated Protein B, Pulmonary Surfactant-Associated Protein C, RNA, Messenger, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Soluble Guanylyl Cyclase, Thyroid Nuclear Factor 1, Time Factors, Transcription Factors
Show Abstract · Added January 20, 2015
Clinical trials demonstrated decreasing rates of bronchopulmonary dysplasia in preterm infants with hypoxic respiratory failure treated with inhaled nitric oxide (iNO). However, the molecular and biochemical effects of iNO on developing human fetal lungs remain vastly unknown. By using a well-characterized model of human fetal alveolar type II cells, we assessed the effects of iNO and hyperoxia, independently and concurrently, on NO-cGMP signaling pathway and differentiation. Exposure to iNO increased cGMP levels by 40-fold after 3 d and by 8-fold after 5 d despite constant expression of phosphodiesterase-5 (PDE5). The levels of cGMP declined significantly on exposure to iNO and hyperoxia at 3 and 5 d, although expression of soluble guanylyl cyclase (sGC) was sustained. Surfactant proteins B and C (SP-B, SP-C) and thyroid transcription factor (TTF)-1 mRNA levels increased in cells exposed to iNO in normoxia but not on exposure to iNO plus hyperoxia. Collectively, these data indicate an increase in type II cell markers when undifferentiated lung epithelial cells are exposed to iNO in room air. However, hyperoxia overrides these potentially beneficial effects of iNO despite sustained expression of sGC.
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1 Members
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23 MeSH Terms
The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.
Friedman EA, Harris PA, Wood AJ, Stein CM, Kurnik D
(2007) Clin Pharmacol Ther 81: 503-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adult, Carbolines, Cold Temperature, Cross-Over Studies, Cyclic Nucleotide Phosphodiesterases, Type 5, Double-Blind Method, Female, Humans, Male, Phosphodiesterase Inhibitors, Raynaud Disease, Regional Blood Flow, Skin, Skin Temperature, Tadalafil, Vasoconstriction
Show Abstract · Added December 10, 2013
Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.
0 Communities
1 Members
0 Resources
17 MeSH Terms
cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.
Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA
(2005) Circ Res 96: 100-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adenoviridae, Adrenergic beta-Agonists, Animals, Carbolines, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 5, Fluorescence Resonance Energy Transfer, Genetic Vectors, Guanylate Cyclase, Isoproterenol, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Second Messenger Systems, Sildenafil Citrate, Soluble Guanylyl Cyclase, Sulfones, Tadalafil
Show Abstract · Added March 4, 2015
Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by N(G)-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, showed no effect of PDE5A inhibition on beta-stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
0 Communities
1 Members
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34 MeSH Terms
Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.
Zhu CB, Hewlett WA, Francis SH, Corbin JD, Blakely RD
(2004) Eur J Pharmacol 504: 1-6
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, CHO Cells, Cricetinae, Cyclic Nucleotide Phosphodiesterases, Type 5, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Phosphodiesterase Inhibitors, Piperazines, Protein Binding, Purines, Rats, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sildenafil Citrate, Sulfones
Show Abstract · Added July 10, 2013
The serotonin (5-hydroxtryptamine, 5-HT) transporter (SERT) plays a critical role in the inactivation of synaptic 5-HT and has been implicated in multiple psychiatric and peripheral disorders. SERT regulation studies demonstrate that activation of cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-linked pathways can increase SERT activity. As cGMP actions are limited by cGMP-specific phosphodiesterase (PDEs), we investigated whether the cGMP-specific PDE5 inhibitor sildenafil (Viagra) can stimulate 5-HT uptake and potentiate cGMP-mediated regulation. In RBL-2H3 cells, SERT activity was stimulated by sildenafil in a concentration- and time-dependent manner. Sildenafil also enhanced the stimulation of SERT triggered by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), effects blocked by the PKG inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8). Sildenafil stimulation of 5-HT uptake arises from an increase in 5-HT transport Vmax and is paralleled by elevated SERT surface antagonist binding, also H8-sensitive. These findings implicate cGMP-targeted PDEs in limiting the regulation of antidepressant-sensitive 5-HT transport.
1 Communities
1 Members
0 Resources
17 MeSH Terms