Genomes and Genes
Nitric Oxide in Pulmonary Hypertension
Principal Investigator: Serpil Erzurum
Abstract: DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure (PAP) and abnormalities in blood vessel growth. The excessive growth of the vascular endothelial cells is the focus of our research. Four years ago, we established methods for culture of pulmonary artery endothelial cells (PAEC) from PAH and donor lungs. The PAEC in culture reflect abnormalities found in PAH lungs and patients in vivo, and made it possible to test our hypotheses in translational mechanistic studies. We found that PAH PAEC have enhanced proliferation &survival, which is dependent on activation of signal transducer and activator of transcription-3 (STAT3), a fundamental regulator of cell survival and angiogenesis. The PAH cells have impaired production of the vasodilator nitric oxide (NO) due to post- translational mechanisms that include phosphorylation/inhibition of endothelial NO synthase (eNOS). In association with low NO, the cells have reduced mitochondria numbers &respiration, which is accompanied by ~3-fold increase in glycolysis for energy production. The shift to anaerobic glycolytic metabolism is related to expression of the pro-survival and pro-angiogenic signal transducer, hypoxia-inducible factor -1a (HIF-1a). Physiologic effects classically ascribed to HIF-expression [increased lung glucose uptake by 18F- fluoro-deoxy-glucose analogue - positron emission tomography (FDG-PET), high-levels of plasma erythropoietin (Epo) and mobilization of bone marrow progenitors] are present in patients and quantitatively associated with PAP. The HIF-expression is mechanistically linked to the alterations in STAT3, NO and Mn superoxide dismutase (MnSOD). Preliminary data show that the PAH PAEC secrete the potent growth- stimulatory &bone marrow-mobilizing hepatocyte growth factor (HGF). Present at high-levels in patient plasma and PAH cell cultures, HGF signals through STAT3 and induces HIF-1a, and is itself induced by STAT3 and increased by hypoxia, which endows the cells with autocrine and paracrine proliferative and pro-angiogenic effects. Here, we hypothesize that PAH endothelial cells have decreased NO production by eNOS and activation of survival pathways STAT3 and HIF-1a. These biochemical mechanisms account for the proliferative, glycolytic, and strongly pro-angiogenic phenotype of the cells. We identify mechanisms of reduced eNOS activity in aim 1, and focus on HIF-expression and mechanisms accounting for its expression in aim 2. In aim 3, we test if HIF-expression is mechanistically important in PAH pathophysiology using the primary cell culture model, a xenograft model of PAH cells in immunodeficient mice and a longitudinal clinical study, in which we test whether experimental outcomes of HIF-effects are associated with clinical outcomes in patients over time. Overall our goals are to define the pathophysiology of the abnormal vascular growth in PAH, and in so doing, apply the knowledge to improve the care of patients. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure and abnormalities in blood vessel growth. The excessive growth of the endothelial cells that line the blood vessels in the lungs of patients afflicted with PAH is the focus of our research. Our studies provide evidence for biochemical and metabolic abnormalities in vascular endothelial cells in PAH, and identify the causal molecular mechanisms. We have found that the PAH endothelial cells have lower than normal production of the vasoregulatory gaseous molecule nitric oxide (NO), and use more than 3-fold greater amounts of glucose for energy production than normal cells. On the basis of our findings, we propose basic biochemical studies, and also test whether measures of glucose uptake in the lung using intravenously injected glucose analogues and positron emission tomography (FDG-PET) are useful to assess lung vascular disease in patients over time. Our goals in this competitive renewal are to define the pathophysiology of the abnormal vascular growth, and in so doing, apply the knowledge to improve the care of patients.
Funding Period: 1999-04-01 - 2014-07-31
more information: NIH RePORT
- Early effect of tidal volume on lung injury biomarkers in surgical patients with healthy lungsAna Fernandez-Bustamante
From the Department of Anesthesiology and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado A F B Department of Anesthesiology and iC42 Integrated Solutions in Systems Biology, University of Colorado School of Medicine, Aurora, Colorado J K, U C Department of Medicine and Webb Waring Center, University of Colorado School of Medicine, Aurora, Colorado J E R Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado A A, T S Department of Pathobiology and Lerner Research Institute NC22, the Cleveland Clinic Foundation and Case Western Reserve University School of Medicine, Cleveland, Ohio A J J, S C E Case Western Reserve University School of Medicine, Cleveland, Ohio C S Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado M M, I S D and Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado Z V T
Anesthesiology 121:469-81. 2014..The authors aimed to characterize the immediate tidal volume (VT)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications...
- Deficiency of lung antioxidants in idiopathic pulmonary arterial hypertensionFares A Masri
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio, USA
Clin Transl Sci 1:99-106. 2008..04). Pulmonary artery pressure (PAP) could be predicted by a regression model incorporating SOD, GPx, and NO(3) values (R(2)= 0.96, p= 0.01). These findings suggest that SOD and GPx are associated with alterations in NO and PAP in IPAH...
- Nitric oxide in adaptation to altitudeCynthia M Beall
Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106, USA
Free Radic Biol Med 52:1123-34. 2012..Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress...
- Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertensionJun Yu
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
J Cell Physiol 228:322-9. 2013..Importantly, the data suggest that caution must be taken when applying ET-1 receptor antagonist therapy to PAH patients...
- Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertensionKewal Asosingh
Pathobiology, Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Blood 120:1218-27. 2012..The results of the present study suggest a causal role for hematopoietic stem cell abnormalities in vascular injury, right ventricular hypertrophy, and morbidity associated with PAH...
- High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4Eileen M Bauer
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, United States of America
Mol Med 18:1509-18. 2012..These data demonstrate that HMGB1-mediated activation of TLR4 promotes experimental PH and identify HMGB1 and/or TLR4 as potential therapeutic targets for the treatment of PH...
- Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertensionSamar Farha
Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Respir Res 14:6. 2013....
- Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 yearErika L Lundgrin
Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
Ann Am Thorac Soc 10:1-9. 2013....
- A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertensionMonal Patel
Department of Pharmacology, Rush University Medical Center, Chicago, Illinois 60612, USA
J Biol Chem 288:25701-16. 2013..Our findings identify a novel GrB-EH(ITSN)-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH...
- Relevant issues in the pathology and pathobiology of pulmonary hypertensionRubin M Tuder
Program in Translational Lung Research, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado Electronic address
J Am Coll Cardiol 62:D4-12. 2013..Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. ..
- Modification of hyaluronan by heavy chains of inter-α-inhibitor in idiopathic pulmonary arterial hypertensionMark E Lauer
From the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195
J Biol Chem 289:6791-8. 2014..CD45-positive leukocytes were identified within these HC-HA matrices. Elevated mRNA levels of the enzyme that transfers HCs to HA, known as tumor necrosis factor-stimulated gene 6, were detected in IPAH lung tissue. ..
- Allergen-induced, eotaxin-rich, proangiogenic bone marrow progenitors: a blood-borne cellular envoy for lung eosinophiliaKewal Asosingh
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA and
J Allergy Clin Immunol 125:918-25. 2010....
- Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalitiesSamar Farha
Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Blood 117:3485-93. 2011....
- Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulationHeng T Duong
Department of Pathobiology, NC22, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Angiogenesis 14:411-22. 2011..This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH...
- Bone morphogenetic protein receptor II is a novel mediator of endothelial nitric-oxide synthase activationArchana Gangopahyay
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
J Biol Chem 286:33134-40. 2011..These data demonstrate a new action of BMPs/BMPRII in the pulmonary endothelium and provide novel mechanistic insight into the pathogenesis of PAH...
- High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertensionIlka Decker
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
Clin Transl Sci 4:253-8. 2011..This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients...
- Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8Kylie M Drake
Genomic Medicine Institute, Cleveland Clinic, OH 44195, USA
Am J Respir Crit Care Med 184:1400-8. 2011..We therefore hypothesized that noncanonical pathways may play an important role in PAH...
- Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in miceEileen M Bauer
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
PLoS ONE 6:e28578. 2011..The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension...
- Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cellsIwona Fijalkowska
Department of Pathology, Johns Hopkins Univesity School of Medicine, Baltimore, MD, USA
Am J Pathol 176:1130-8. 2010..These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1alpha expression and account for lower numbers of mitochondria in IPAH-ECs...
- Ventricular geometry, strain, and rotational mechanics in pulmonary hypertensionSarinya Puwanant
Department of Cardiovascular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Circulation 121:259-66. 2010..We tested the hypothesis that right ventricular (RV) pressure overload affects RV function and further influences left ventricular (LV) geometry, which adversely affects LV twist mechanics and segmental function...
- Pivotal role of c-Fos in nitric oxide synthase 2 expression in airway epithelial cellsArnaud Chambellan
INSERM, UMR915, l institut du thorax, Nantes F 44000, France
Nitric Oxide 20:143-9. 2009..Overall, these studies indicate that c-Fos is a requisite and specific component for inducible NOS2 expression...
- Elevated pulmonary artery pressure among Amhara highlanders in EthiopiaBrian D Hoit
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 7125, USA
Am J Hum Biol 23:168-76. 2011..The objective of this study was to identify the consequences of lifelong hypoxia exposure for the pulmonary vasculature among Amhara high-altitude natives from Ethiopia...
- Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlandersBrian D Hoit
Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106 5038, USA
J Appl Physiol (1985) 99:1796-801. 2005....
- Abnormalities in nitric oxide and its derivatives in lung cancerFares A Masri
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
Am J Respir Crit Care Med 172:597-605. 2005..Reactive nitrogen species formed from nitric oxide (NO) or its metabolites, can lead to protein tyrosine nitration, which is elevated in lung cancer...
- Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosisTobias Peikert
Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Cancer Res 66:4693-700. 2006..028) in 293/MAGE-A4 cells. These findings suggest that MAGE-A4 expression may promote tumor cell death, sensitize malignancies to apoptotic stimuli, such as chemotherapeutic agents, and therefore may represent a tumor suppressor protein...
- Gene expression profile of human airway epithelium induced by hyperoxia in vivoArnaud Chambellan
Institut du Thorax, INSERM U533, Faculte de Medecine, Nantes, France
Am J Respir Cell Mol Biol 35:424-35. 2006..Thus, the human airway early response to hyperoxia relies predominantly upon induction of cytoprotective chaperones and the ubiquitin-proteasome-dependent protein degradation system to maintain airway homeostatic integrity...
- Role of epithelial nitric oxide in airway viral infectionWeiling Xu
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, NC 20, Cleveland, OH 44195, USA
Free Radic Biol Med 41:19-28. 2006..Hosts deficient in NO synthesis, such as those patients with cystic fibrosis, have impaired antiviral defense and may benefit from therapies to augment NO levels in the airways...
- Inactivation of neuregulin-1 by nitrationDavid E Nethery
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals of Cleveland, Wearn 610, 11100 Euclid Avenue, Cleveland, OH 44106, USA
Am J Physiol Lung Cell Mol Physiol 292:L287-93. 2007..Posttranslational nitration of growth factors in states where reactive nitrogen species are increased may be an important means of regulating growth factor receptor effects in the lung...
- Effect of dexamethasone on atrial fibrillation after cardiac surgery: prospective, randomized, double-blind, placebo-controlled trialJean Pierre Yared
Department of Cardiothoracic Anesthesiology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
J Cardiothorac Vasc Anesth 21:68-75. 2007..The purpose of this study was to assess the effect of preoperative dexamethasone (DEX) on the occurrence of postoperative atrial fibrillation (AF)...
- Th1- and Th2-dependent endothelial progenitor cell recruitment and angiogenic switch in asthmaKewal Asosingh
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
J Immunol 178:6482-94. 2007..Thus, a Th1- and Th2-dependent angiogenic switch with EPC mobilization, recruitment, and increased lung vessel formation occurs early but becomes a sustained and cumulative component of the allergen-induced asthmatic response...
- Two routes to functional adaptation: Tibetan and Andean high-altitude nativesCynthia M Beall
Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106, USA
Proc Natl Acad Sci U S A 104:8655-60. 2007..Identifying the genetic bases of these traits is crucial to discovering the steps along the Tibetan and Andean routes to functional adaptation...
- Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertensionFares A Masri
Department of Pathobiology, Allergy and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
Am J Physiol Lung Cell Mol Physiol 293:L548-54. 2007..Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs...
- Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycleSamar Farha
Department of Pulmonary, Allergy, and Critical Care Medicine, Cleveland Clinic, Cleveland, OH, USA
J Appl Physiol 103:1789-95. 2007..These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle...
- Signal transduction and oxidative processes in sinonasal polyposisSteven B Cannady
Head and Neck Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
J Allergy Clin Immunol 120:1346-53. 2007..Based on its critical role in mediating cell growth and antimicrobial function, decrease of NO levels has been implicated in the pathogenesis of nasal polyposis...
- Higher blood flow and circulating NO products offset high-altitude hypoxia among TibetansS C Erzurum
Department of Pathobiology, Allergy, and Critical Care, Cleveland Clinic, Cleveland, OH 44195, USA
Proc Natl Acad Sci U S A 104:17593-8. 2007..These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia...
- Circulating angiogenic precursors in idiopathic pulmonary arterial hypertensionKewal Asosingh
Cleveland Clinic, Department of Pathobiology, NC22, 9500 Euclid Ave, Cleveland, OH 44195, USA
Am J Pathol 172:615-27. 2008..Thus, mobilization of high levels of proliferative bone marrow-derived proangiogenic precursors is a characteristic of IPAH and may participate in the pulmonary vascular remodeling process...
- Effects of the menstrual cycle on lung function variables in women with asthmaSamar Farha
Respiratory Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
Am J Respir Crit Care Med 180:304-10. 2009..One vital function modulated over the menstrual cycle in healthy women is gas transfer, and this has been related to angiogenesis and cyclic expansion of the pulmonary vascular bed...
- Angioplasticity in asthmaKewal Asosingh
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Biochem Soc Trans 37:805-10. 2009..This mini review provides a concise synopsis of our present knowledge about vascular plasticity in adult lungs, summarizes our current view of angioplasticity in asthma and highlights yet unresolved areas of potential interest...
- The regulation and role of extracellular glutathione peroxidaseSuzy A A Comhair
Department of Pulmonary and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Antioxid Redox Signal 7:72-9. 2005..Induction of extracellular glutathione peroxidase occurs in airway inflammation and undoubtedly plays an important defense against oxidative injury to the airway surface...