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Blood, 1 April 2007, Vol. 109, No. 7, pp. 3088-3098. Prepublished online as a Blood First Edition Paper on December 7, 2006; DOI 10.1182/blood-2006-08-039438. This Article Full Text (PDF) Erratum (v111,p1772) All Versions of this Article: blood-2006-08-039438v1 109/7/3088    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hsu, L. L. Articles by Gladwin, M. T. Search for Related Content PubMed PubMed Citation Articles by Hsu, L. L. Articles by Gladwin, M. T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 3, 2006 Accepted November 22, 2006 Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability Lewis L. Hsu*, Hunter C. Champion, Sally A. Campbell-Lee, Trinity J. Bivalacqua, Elizabeth A. Manci, Bhalchandra A. Diwan, Daniel M. Schimel, Audrey E. Cochard, Xunde Wang, Alan N. Schechter, Constance T. Noguchi, and Mark T. Gladwin Marian Anderson Sickle Cell Center at St. Christopher's Hospital for Children, Drexel University, Philadelphia, PA Johns Hopkins University, Baltimore, MD Transfusion Medicine, Department of Pathology, University of Illinois at Chicago, Chicago, IL Sickle Cell Pathology Unit, University of South Alabama, Mobile, AL Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD Mouse Imaging Facility, National Institute of Neurologic Disorders and Stroke, NIH, Bethesda, MD Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD Molecular Medicine Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, Bethesda, MD * Corresponding author; email: pandasickle{at}yahoo.com. Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiological mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By micro-cardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors and endothelium-dependent vasodilators, and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO-axis: impaired constitutive nitric oxide synthase activity with loss of eNOS dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a non-sickle mouse model of acute alloimmune hemolysis. Though the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The "NO" tipping point Gregory M. Vercellotti Blood 2007 109: 2675. [Full Text] [PDF] This article has been cited by other articles: A. C. Frei, Y. Guo, D. W. Jones, K. A. Pritchard Jr, K. A. Fagan, N. Hogg, and N. J. Wandersee Vascular dysfunction in a murine model of severe hemolysis Blood, July 15, 2008; 112(2): 398 - 405. [Abstract] [Full Text] [PDF] M. L. Krajewski, L. L. Hsu, and M. T. Gladwin The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H4 - H7. [Full Text] [PDF] D. K. Kaul, X. Zhang, T. Dasgupta, and M. E. Fabry Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H39 - H47. [Abstract] [Full Text] [PDF] A. E. Ashley-Koch, L. Elliott, M. E. Kail, L. M. De Castro, J. Jonassaint, T. L. Jackson, J. Price, K. I. Ataga, M. C. Levesque, J. B. Weinberg, et al. Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease Blood, June 15, 2008; 111(12): 5721 - 5726. [Abstract] [Full Text] [PDF] L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice FASEB J, June 1, 2008; 22(6): 1849 - 1860. [Abstract] [Full Text] [PDF] D. R. Archer, J. K. Stiles, G. W. Newman, A. Quarshie, L. L. Hsu, P. Sayavongsa, J. Perry, E. M. Jackson, and J. M. Hibbert C-Reactive Protein and Interleukin-6 Are Decreased in Transgenic Sickle Cell Mice Fed a High Protein Diet J. Nutr., June 1, 2008; 138(6): 1148 - 1152. [Abstract] [Full Text] [PDF] R. Grubina, S. Basu, M. Tiso, D. B. Kim-Shapiro, and M. T. Gladwin Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity J. Biol. Chem., February 8, 2008; 283(6): 3628 - 3638. [Abstract] [Full Text] [PDF] C. R. Morris, J. H. Suh, W. Hagar, S. Larkin, D. A. Bland, M. H. Steinberg, E. P. Vichinsky, M. Shigenaga, B. Ames, F. A. Kuypers, et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease Blood, January 1, 2008; 111(1): 402 - 410. [Abstract] [Full Text] [PDF] P. Pokreisz, G. Marsboom, and S. Janssens Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension: the right heart revisited Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H75 - H84. [Abstract] [Full Text] [PDF] R. I. Liem, L. T. Young, and A. A. Thompson Tricuspid regurgitant jet velocity is associated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension Haematologica, November 1, 2007; 92(11): 1549 - 1552. [Abstract] [Full Text] [PDF]

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