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Candice D Fike - One of the best experts on this subject based on the ideXlab platform.

  • combined l citrulline and tetrahydrobiopterin therapy improves no signaling and ameliorates chronic hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2020
    Co-Authors: Anna Dikalova, Judy L Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham
    Abstract:

    Newborn pigs with chronic Hypoxia-Induced Pulmonary Hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS...

  • tetrahydrobiopterin oral therapy recouples enos and ameliorates chronic hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Anna Dikalova, Judy L Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar
    Abstract:

    We previously showed that newborn piglets who develop Pulmonary Hypertension during exposure to chronic hypoxia have diminished Pulmonary vascular nitric oxide (NO) production and evidence of endot...

  • rescue treatment with l citrulline inhibits hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Respiratory Cell and Molecular Biology, 2014
    Co-Authors: Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham, Anna Dikalova, Judy L Aschner
    Abstract:

    Infants with cardioPulmonary disorders associated with hypoxia develop Pulmonary Hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates Pulmonary Hypertension in newborn piglets. Rescue treatments, initiated after the onset of Pulmonary Hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of Pulmonary Hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and Pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in Pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic Hypoxia-Induced Pulmonary Hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse Pulmonary Hypertension in infants suffering from cardioPulmonary conditions associated with hypoxia.

  • prolonged hypoxia augments l citrulline transport by system a in the newborn piglet Pulmonary circulation
    Cardiovascular Research, 2012
    Co-Authors: Michael Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham, Marta Sidorykwegrzynowicz, Lawrence S Prince
    Abstract:

    Aims Pulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of l-arginine from intracellular l-citrulline but do not express the enzymes needed for de novo l-citrulline synthesis. Hence, l-citrulline levels in PAECs are dependent on l-citrulline transport. Once generated, l-arginine can be converted to l-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to Pulmonary Hypertension, alters the transport of l-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. Methods and results PAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and 14C-l-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. 14C-l-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased 14C-l-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and l-citrulline levels in lungs of piglets with chronic Hypoxia-Induced Pulmonary Hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher l-citrulline levels than lungs from controls. Conclusion Increased SNAT1 expression and the concomitant enhanced ability to transport l-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic Hypoxia-Induced Pulmonary Hypertension in newborns.

  • l citrulline ameliorates chronic hypoxia induced Pulmonary Hypertension in newborn piglets
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2009
    Co-Authors: Madhumita Ananthakrishnan, Mark R Kaplowitz, Yongmei Zhang, Frederick E Barr, Marshall L Summar, Heidi A B Smith, Gary Cunningham, Jordan A Magarik, Candice D Fike
    Abstract:

    Newborn piglets develop Pulmonary Hypertension and have diminished Pulmonary vascular nitric oxide (NO) production when exposed to chronic hypoxia. NO is produced by endothelial NO synthase (eNOS) in the Pulmonary vascular endothelium using l-arginine as a substrate and producing l-citrulline as a byproduct. l-Citrulline is metabolized to l-arginine by two enzymes that are colocated with eNOS in Pulmonary vascular endothelial cells. The purpose of this study was to determine whether oral supplementation with l-citrulline during exposure of newborn piglets to 10 days of chronic hypoxia would prevent the development of Pulmonary Hypertension and increase Pulmonary NO production. A total of 17 hypoxic and 17 normoxic control piglets were studied. Six of the 17 hypoxic piglets were supplemented with oral l-citrulline starting on the first day of hypoxia. l-Citrulline supplementation was provided orally twice a day. After 10 days of hypoxia or normoxia, the animals were anesthetized, hemodynamic measurements were performed, and the lungs were perfused in situ. Pulmonary arterial pressure and Pulmonary vascular resistance were significantly lower in hypoxic animals treated with l-citrulline compared with untreated hypoxic animals (P < 0.001). In vivo exhaled NO production (P = 0.03) and nitrite/nitrate accumulation in the perfusate of isolated lungs (P = 0.04) were significantly higher in l-citrulline-treated hypoxic animals compared with untreated hypoxic animals. l-Citrulline supplementation ameliorated the development of Pulmonary Hypertension and increased NO production in piglets exposed to chronic hypoxia. We speculate that l-citrulline may benefit neonates exposed to prolonged periods of hypoxia from cardiac or Pulmonary causes.

Kai Yang - One of the best experts on this subject based on the ideXlab platform.

Mark R Kaplowitz - One of the best experts on this subject based on the ideXlab platform.

  • combined l citrulline and tetrahydrobiopterin therapy improves no signaling and ameliorates chronic hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2020
    Co-Authors: Anna Dikalova, Judy L Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham
    Abstract:

    Newborn pigs with chronic Hypoxia-Induced Pulmonary Hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS...

  • tetrahydrobiopterin oral therapy recouples enos and ameliorates chronic hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Anna Dikalova, Judy L Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar
    Abstract:

    We previously showed that newborn piglets who develop Pulmonary Hypertension during exposure to chronic hypoxia have diminished Pulmonary vascular nitric oxide (NO) production and evidence of endot...

  • Pediatric Pulmonology 40:72–80 (2005) Sildenafil and an Early Stage of Chronic Hypoxia-Induced Pulmonary Hypertension in Newborn Piglets
    2015
    Co-Authors: Karen M. Binns-loveman, Mark R Kaplowitz, Ice D. Fike
    Abstract:

    Summary. Devising therapies that might prevent the onset or progression of Pulmonary hyper-tension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic Hypoxia-Induced Pulmonary Hypertension in newborn pigs. Another objective was to determine whether sildenafil causes Pulmonary vasodilation without systemic vasodilation in pigletswith chronic Pulmonary Hypertension. Pigletswere raised in roomair (control, n 5) or 10– 11 % O2 (hypoxic, n17) for 3 days. Some piglets (n4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and Pulmonary arterial pressure (Ppa), Pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n 6) or placebo (n 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic Hypoxia-Induced Pulmonary Hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic Hypoxia-Induced Pulmonary Hypertension in newborn piglets. However, a single oral dose of sildenafil caused Pulmonary vasodilation, without systemic vaso-dilation, in piglets with chronic Hypoxia-Induced Pulmonary Hypertension, which may have therapeutic implications. Pediatr Pulmonol. 2005; 40:72–80. 2005 Wiley-Liss, Inc. Key words: Pulmonary circulation; nitric oxide pathway; phosphodiesterase inhibitors; selective Pulmonary dilation; cyclic GMP; Pulmonary vascular resistance

  • rescue treatment with l citrulline inhibits hypoxia induced Pulmonary Hypertension in newborn pigs
    American Journal of Respiratory Cell and Molecular Biology, 2014
    Co-Authors: Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham, Anna Dikalova, Judy L Aschner
    Abstract:

    Infants with cardioPulmonary disorders associated with hypoxia develop Pulmonary Hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates Pulmonary Hypertension in newborn piglets. Rescue treatments, initiated after the onset of Pulmonary Hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of Pulmonary Hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and Pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in Pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic Hypoxia-Induced Pulmonary Hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse Pulmonary Hypertension in infants suffering from cardioPulmonary conditions associated with hypoxia.

  • prolonged hypoxia augments l citrulline transport by system a in the newborn piglet Pulmonary circulation
    Cardiovascular Research, 2012
    Co-Authors: Michael Aschner, Mark R Kaplowitz, Candice D Fike, Marshall L Summar, Gary Cunningham, Marta Sidorykwegrzynowicz, Lawrence S Prince
    Abstract:

    Aims Pulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of l-arginine from intracellular l-citrulline but do not express the enzymes needed for de novo l-citrulline synthesis. Hence, l-citrulline levels in PAECs are dependent on l-citrulline transport. Once generated, l-arginine can be converted to l-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to Pulmonary Hypertension, alters the transport of l-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. Methods and results PAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and 14C-l-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. 14C-l-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased 14C-l-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and l-citrulline levels in lungs of piglets with chronic Hypoxia-Induced Pulmonary Hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher l-citrulline levels than lungs from controls. Conclusion Increased SNAT1 expression and the concomitant enhanced ability to transport l-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic Hypoxia-Induced Pulmonary Hypertension in newborns.

Christos Samakovlis - One of the best experts on this subject based on the ideXlab platform.

  • a rassf1a hif1α loop drives warburg effect in cancer and Pulmonary Hypertension
    Nature Communications, 2019
    Co-Authors: Swati Dabral, Gregg L Semenza, Christian Muecke, Chanil Valasarajan, Mario Schmoranzer, Astrid Wietelmann, Michael Meister, Thomas Muley, Tamina Seegernukpezah, Christos Samakovlis
    Abstract:

    Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary Hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental Hypoxia-Induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer. Pulmonary Hypertension is characterized by a metabolic switch similar to the Warburg effect in cancer. Here Dabral et al. describe a RASSF1a-HIF-1α feedforward loop driving the Warburg effect both in a mouse model of Hypoxia-Induced Pulmonary Hypertension and a subset of human cancer cells.

  • A RASSF1A-HIF1α loop drives Warburg effect in cancer and Pulmonary Hypertension
    Nature Publishing Group, 2019
    Co-Authors: Swati Dabral, Gregg L Semenza, Christian Muecke, Chanil Valasarajan, Mario Schmoranzer, Astrid Wietelmann, Michael Meister, Thomas Muley, Tamina Seeger-nukpezah, Christos Samakovlis
    Abstract:

    Pulmonary Hypertension is characterized by a metabolic switch similar to the Warburg effect in cancer. Here Dabral et al. describe a RASSF1a-HIF-1α feedforward loop driving the Warburg effect both in a mouse model of Hypoxia-Induced Pulmonary Hypertension and a subset of human cancer cells

Usha J Raj - One of the best experts on this subject based on the ideXlab platform.

  • smooth muscle insulin like growth factor 1 mediates hypoxia induced Pulmonary Hypertension in neonatal mice
    American Journal of Respiratory Cell and Molecular Biology, 2016
    Co-Authors: Miranda Sun, Qiwei Yang, Ramaswamy Ramchandran, Jiwang Chen, Usha J Raj
    Abstract:

    Insulin-like growth factor (IGF)-1 is a potent mitogen of vascular smooth muscle cells (SMCs), but its role in Pulmonary vascular remodeling associated with Pulmonary Hypertension (PH) is not clear. In an earlier study, we implicated IGF-1 in the pathogenesis of Hypoxia-Induced PH in neonatal mice. In this study, we hypothesized that Hypoxia-Induced up-regulation of IGF-1 in vascular smooth muscle is directly responsible for Pulmonary vascular remodeling and PH. We studied neonatal and adult mice with smooth muscle-specific deletion of IGF-1 and also used an inhibitor of IGF-1 receptor (IGF-1R), OSI-906, in neonatal mice. We found that, in neonatal mice, SMC-specific deletion of IGF-1 or IGF-1R inhibition with OSI-906 attenuated Hypoxia-Induced Pulmonary vascular remodeling in small arteries, right ventricular hypertrophy, and right ventricular systolic pressure. Pulmonary arterial SMCs from IGF-1-deleted mice or after OSI-906 treatment exhibited reduced proliferative potential. However, in adult mice, smooth muscle-specific deletion of IGF-1 had no effect on Hypoxia-Induced PH. Our data suggest that vascular smooth muscle-derived IGF-1 plays a critical role in Hypoxia-Induced PH in neonatal mice but not in adult mice. We speculate that the IGF-1/IGF-1R axis is important in pathogenesis of PH in the developing lung and may be amenable to therapeutic manipulation in this age group.

  • igf 1 signaling in neonatal hypoxia induced Pulmonary Hypertension role of epigenetic regulation
    Vascular Pharmacology, 2015
    Co-Authors: Qiwei Yang, Miranda Sun, Ramaswamy Ramchandran, Usha J Raj
    Abstract:

    Pulmonary Hypertension is a fatal disease characterized by a progressive increase in Pulmonary artery pressure accompanied by Pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal Hypoxia-Induced Pulmonary Hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of Hypoxia-Induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in Pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKTS473 is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in Pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal Hypoxia-Induced global DNA methylation levels in lungs and specific cytosine methylation levels around the Pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic Hypoxia-Induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and Pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of Pulmonary Hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of Hypoxia-Induced PH and warrants further study of the role of IGF-1 in neonatal Pulmonary hypertensive disease.

  • adenosine monophosphate activated protein kinase is required for Pulmonary artery smooth muscle cell survival and the development of hypoxic Pulmonary Hypertension
    American Journal of Respiratory Cell and Molecular Biology, 2013
    Co-Authors: Joyce Christina F Ibe, Jason X J Yuan, Qiyuan Zhou, Tianji Chen, Haiyang Tang, Usha J Raj, Guofei Zhou
    Abstract:

    Human Pulmonary artery smooth muscle cells (HPASMCs) express both adenosine monophosphate–activated protein kinase (AMPK) α1 and α2. We investigated the distinct roles of AMPK α1 and α2 in the survival of HPASMCs during hypoxia and Hypoxia-Induced Pulmonary Hypertension (PH). The exposure of HPASMCs to hypoxia (3% O2) increased AMPK activation and phosphorylation, and the inhibition of AMPK with Compound C during hypoxia decreased their viability and increased lactate dehydrogenase activity and apoptosis. Although the suppression of either AMPK α1 or α2 expression led to increased cell death, the suppression of AMPK α2 alone increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. It also resulted in the decreased expression of myeloid cell leukemia sequence 1 (MCL-1). The knockdown of MCL-1 or MCL-1 inhibitors increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. On the other hand, the suppression of AMPK α1 expression alone prevented hypoxia-mediated autophagy. The i...