Pulmonary hypertension and nitric oxide depletion in sickle cell disease

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 687-692 ◽  
Author(s):  
H. Franklin Bunn ◽  
David G. Nathan ◽  
George J. Dover ◽  
Robert P. Hebbel ◽  
Orah S. Platt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Association Studies ◽  
Large Body ◽  
Clinical Manifestations ◽  
Cell Disease ◽  
Plasma Hemoglobin ◽  
Order Of Magnitude

During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.

scholarly journals Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 3088-3098 ◽  
Author(s):  
Lewis L. Hsu ◽  
Hunter C. Champion ◽  
Sally A. Campbell-Lee ◽  
Trinity J. Bivalacqua ◽  
Elizabeth A. Manci ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Time Course ◽  
Cell Disease ◽  
Plasma Hemoglobin ◽  
Constitutive Nitric Oxide Synthase ◽  
Oxide Synthase

Abstract Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac 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 (NOS) with loss of endothelial NOS (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 nonsickle mouse model of acute alloimmune hemolysis. Although 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.

The Arginine-to-Ornithine Ratio: Biomarker of Arginase Activity and Predictor of Mortality in Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 237-237 ◽  
Author(s):  
Claudia R. Morris ◽  
Gregory Kato ◽  
Mirjana Poljakovic ◽  
William C. Blackwelder ◽  
Stan Hazen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Risk Ratio ◽  
Arginase Activity ◽  
Nitric Oxide Production ◽  
Cell Disease ◽  
Arginine Metabolism

Abstract Sickle cell disease (SCD) is characterized by a state of nitric oxide resistance and limited bioavailability of L-arginine, the substrate for nitric oxide synthesis. While nitric oxide resistance occurs secondary to inactivation of nitric oxide by plasma hemoglobin released during intravascular hemolysis and by reactive oxygen species, mechanisms that limit L-arginine are not known. We hypothesized that increased arginase activity in patients with SCD would shift arginine metabolism away from nitric oxide production and towards ornithine metabolism, contributing to endothelial dysfunction and the development of pulmonary hypertension. Furthermore, since arginine and ornithine compete for the same transport system for cellular uptake, a decrease in the Arginine-to-Ornithine ratio resulting from increased arginase activity could also impair arginine bioavailability for nitric oxide production. Our goal was to evaluate associations between plasma arginase, arginine metabolism and pulmonary hypertension and prospective mortality in SCD. Plasma and erythrocyte arginase activity and amino acid levels were determined for patients with SCD and compared to ethnically matched control subjects. A diagnosis of pulmonary hypertension by Doppler-echocardiogram and prospective mortality were determined over 30 months of sequential patient enrollment. Plasma arginase activity was significantly elevated in patients with SCD compared to controls (2.2±2, n=140 vs. 0.4±2 μmol/ml/hr, n=45, p=0.007), trending higher in subjects with pulmonary hypertension. Plasma arginase activity correlated with the Arginine-to-Ornithine ratio (r=−0.33, p=0.0004), and lower ratios were associated with greater severity of pulmonary hypertension (1.1±0.4 vs. 0.8±0.4 vs. 0.6±0.3, controls vs. SCD without pulmonary hypertension vs. SCD with pulmonary hypertension, respectively, p=0.01) and independently associated with mortality (0.7±0.4 vs. 0.5±0.2, alive vs. dead, p=0.003; Risk Ratio = 4.9 [CI: 1.4, 17.1], p=0.002, for a low Arginine-to-Ornithine ratio; 13 deaths total). The mortality risk ratio increased to 7.0 ([CI: 1.6, 31.6], p=0.01), when the Arginine-to-Ornithine ratio was adjusted for creatinine, likely reflecting the impact of renal disease. Plasma arginase activity correlated with markers of increased hemolytic rate, including LDH (r=0.44, p<0.001), AST (r=0.39, p<0.002), reticulocyte count (r=0.25, p<0.001), and Hct (r= −0.25, p<0.001), and was higher in erythrocytes of SCD patients compared to controls (37.7±2.9, n=16 vs 23.5±1.7 nmol/mg/min, n=45, p<0.0001), consistent with hemolytic release of erythrocyte arginase. These data support a novel mechanism of disease whereby hemolysis not only liberates vasoactive hemoglobin but also releases erythrocyte arginase, which contributes to impaired nitric oxide bioavailability, endothelial dysfunction, pulmonary hypertension and death. The Arginine-to-Ornithine ratio, a reflection of arginase activity, may represent a useful biomarker of disease severity and risk of death in patients with SCD.

Arginine Metabolite Profiling in Sickle Cell Disease: Abnormal Levels and Correlations with Pulmonary Hypertension, Desaturation, Hemolysis and Organ Dysfunction.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1205-1205
Author(s):  
Gregory J. Kato ◽  
Wang Zeneng ◽  
James G. Taylor ◽  
Roberto F. Machado ◽  
William C. Blackwelder ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Renal Dysfunction ◽  
Sickle Cell ◽  
Early Mortality ◽  
Systemic Hypertension ◽  
Cell Disease ◽  
Intravascular Hemolysis ◽  
Arginine Transport

Abstract Pulmonary arterial hypertension (PAH) in patients with sickle cell disease (SCD) is linked to intravascular hemolysis, renal dysfunction, systolic hypertension, cholestasis, and early mortality. Although the pathophysiology of PAH in SCD is multifactorial, one important and fundamental factor is impaired nitric oxide bioavailability. Severe intravascular hemolysis releases hemoglobin and arginase into blood plasma, leading to consumption of nitric oxide and its plasma precursor L-arginine, the obligate substrate for the nitric oxide synthases (NOS). In order to explore other potential alterations in the arginine pathway that might affect arginine bioavailability and nitric oxide production, we used high-performance liquid chromatography-tandem mass spectrometry to determine the plasma concentrations for several key metabolites that may affect NOS activity or arginine transport: asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), N-monomethyl-L-arginine (MMA), and N-ω-hydroxy-L-arginine (NOHA). Plasma levels of ADMA, SDMA and MMA are significantly higher in all forms of SCD than in healthy African American control subjects (Table 1). NOHA, the intermediate species in nitric oxide synthesis from L-arginine, is significantly lower in sickle-β-thalassemia (Sβ-thal) patients and homozygous SCD (SS). L-arginine levels are significantly lower in all forms of SCD, as previously reported. PAH as assessed by echocardiography screening was correlated to SDMA (r=0.30, p<0.0001) and NOHA (r=0.23, p=0.002). Similar correlations were observed to NT-proBNP, another marker of PAH. Low oxygen saturations were linked to high levels of all four arginine metabolites. ADMA levels were elevated with severe hemolysis, and unexpectedly lower with renal dysfunction. Levels of SDMA and NOHA were significantly related to renal dysfunction (p<0.01), with an additional link of NOHA to systemic hypertension (p<0.001). In addition, Cox proportional hazard analysis showed a relationship of the arginine/SDMA ratio to early mortality (p<0.001). In summary, levels of the endogenous NOS inhibitor ADMA are highly elevated in SCD and linked to hemolysis, and may contribute to hemolysis-associated endothelial dysfunction. The levels of SDMA, a competitive inhibitor of arginine transport and intracellular bioavailability, are also elevated and linked to PAH, desaturation, renal dysfunction and early mortality risk. The low levels of arginine and NOHA in SCD are consistent with low substrate availability for NOS, and may also limit NO production. The role of arginine metabolites in dysregulation of the arginine-nitric oxide axis and pulmonary hypertension in SCD merits further investigation. Table 1. Arginine Metabolites in Sickle Cell Disease compared to controls. Metabolite Control (n=29) SC (n=34) Sβ-thal (n=11) SS (n=130) Values indicate median values in μM. *p<0.05; **p<0.01; ***p<0.001, Mann-Whitney test compared to controls. ADMA 0.31 0.82*** 0.92* 0.99*** SDMA 0.83 0.92* 1.03** 1.03*** MMA 0.13 0.15* 0.20** 0.18*** NOHA 2.50 2.23 2.15* 1.80** L-Arginine 78.3 51.5*** 41.6*** 45.5***

Sickle Cell Pulmonary Hypertension and Dysregulated NO Axis in a Mouse Model Are Modulated by Apolipoprotein a-1 Availability

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2499-2499
Author(s):  
Lewi s L. Hsu ◽  
Hazim El-Haddad ◽  
Marcelo Amar ◽  
Gregory J. Kato ◽  
Alan T Remaley ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxidant Stress ◽  
Cell Disease ◽  
Plasma Hemoglobin ◽  
Apolipoprotein A ◽  
Oxide Synthase

Abstract We have recently shown that the pulmonary hypertension and pulmonary vascular response impairment in models of sickle cell disease are associated with a dysregulation of nitric oxide synthase (NOS) coupling and cGMP signaling. However, the pathophysiologic mechanisms and exacerbating factors leading to pulmonary vasculopathy remain unclear. In the present study, we investigated the effect of sickle cell disease in the context of ApoE deficient mice (ApoEKO) that express advanced atherosclerosis and mice that express the protective ApoA-1 protein (TgApoA1) that received bone marrow transplant with sickle cell marrow. HYPOTHESES: Mice with low ApoA-1 and sickle red blood cells will have higher oxidant stress than sickle cell mice, increasing the severity of development of pulmonary vasculopathy. High levels of ApoAI should protect mice with sickle red blood cells by reducing the oxidant stress and pulmonary hypertension. METHODS: Bone marrow harvested from “Berkeley” sickle cell mouse donors were transplanted into 3 groups of myeloablatively irradiated recipients: Tg ApoA1 mice with high HDL levels, ApoE knockout (ApoEKO) mice with high VLDL/IDL plasma levels, and wild-type mice. Mice received routine rodent chow. Half of the recipients were studied by closed-chest cardiac catheterization soon after marrow engraftment (11 wks after BMT) and the other half studied 3 months later. Blood samples were obtained for measurement of CBC/reticulocyte count, LDH, plasma hemoglobin, and total cholesterol. Tissue samples were assayed for NOS activity and dimerization. RESULTS: Mice transplanted with SS marrow showed significant 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. The baseline pulmonary hypertension and endothelial dysfunction was augmented in ApoEKO+SS mice, but this added impairment was abrogated in TgApoA1+SS mice. However, endothelium-independent vasodilation in all mice was normal. Mechanisms of this vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide all of which were markedly augmented in ApoEKO-SS and improved in TgApoA1-SS mice when compared to ApoEKO-SS mice. In addition, vascular arginase levels were markedly higher in ApoEKO-SS mice (~50%, P<0.05 vs ApoEKO controls and ~40% vs SS mice) suggesting an increased reaction to sickle cell/hemolysis in ApoE deficient conditions. CONCLUSION: Adjusting chronic apolipoprotein A-1 levels can modulate the pulmonary hypertension and endothelial dysfunction in this sickle cell animal model. Depleting ApoA-1 may serve as a mechanism for further inhibition of NOS activity in SS disease. These animal model data provide a mechanistic basis for our epidemiologic observations that low ApoA-1 and low HDL are associated with more severe pulmonary hypertension in sickle cell patients. Conversely, these data extend the observations of Ou and Pritchard that acute administration of LF4, an ApoA-1 mimetic, improves arterial vaso-reactivity in a similar sickle cell mouse model. Taken together, these preclinical data indicate that ApoA-1 deserves further study as a potential therapy for the global dysregulation of the NO axis in SCD.

Nitric Oxide Effects in Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-48-sci-48
Author(s):  
Lori Styles
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxidant Stress ◽  
Cell Disease ◽  
No Donors ◽  
Skin Ulcers ◽  
No Bioavailability ◽  
Inhaled No

Sickle cell disease (SCD) is a complex hemoglobinopathy characterized by microvascular occlusion and hemolytic anemia. Patients suffer from a myriad of both acute and chronic problems affecting virtually every organ system. Historically, microvascular occlusion has been the focus of scientific investigations into these manifestations and the chronic hemolysis of SCD was overlooked. More recently, however, the importance of the pathophysiology of hemolysis has been appreciated and related to a subset of the clinical manifestations of SCD, including pulmonary hypertension, priapism, skin ulcers, and possibly stroke. This subphenotype of SCD has been convincingly related to impaired nitric oxide (NO) homeostasis due to hemolysis. NO has pleiotropic effects including vaso-dilatory, antioxidative, anti-adhesion, and anti-thrombotic properties, which are all potentially important in the pathophysiology of SCD. Perturbation of NO homeostasis, therefore, could profoundly impact patients with SCD. Animal and human data support a state of “NO resistance” in SCD patients. Human studies have shown that SCD patients have a decreased response to exogenous NO donors and that is likely due to the scavenging of NO by free plasma hemoglobin that results from ongoing hemolysis. “NO resistance” is further augmented by the increased levels of reactive oxygen species (ROS) known to occur in SCD patients. High levels of ROS favor additional hemolysis through increased oxidant stress on the sickle red blood cell and reduce NO bioavailability by inactivation of circulating NO. With the substantial human and animal data to support a role for “NO resistance” in the pathophysiology of SCD, investigation with NO-based therapy have begun. Several approaches to overcoming “NO resistance” can be devised including increasing the precursors to NO, decreasing hemolysis, direct NO donors, and decreasing oxidant stress. To date, studies evaluating arginine (NO precursor), inhaled NO, and sildenafil (NO donor) have been reported. Oral arginine showed no benefit in a large clinical trial, and a preliminary trial of inhaled NO had only minimal benefit. Sildenafil may be more promising and is under further study. Lastly, although impaired NO bioavailability has been related to a subset of patients with pulmonary hypertension, skin ulcers and priapism, it will be important to determine what impact NO has on other manifestations, such as vaso-occlusive pain episodes and whether NO modulation can also be used therapeutically in this setting.

TSP1-CD47 Signaling Modulates the Severity of Pulmonary Hypertension in a Mouse Model of Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 898-898
Author(s):  
Enrico M Novelli ◽  
Mingyi Yao ◽  
Xiaojun Huang ◽  
Jeffrey Baust ◽  
Hunter Champion ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Sickle Cell ◽  
Systolic Pressure ◽  
Cell Disease ◽  
C57bl Mice ◽  
No Signaling

Abstract Abstract 898 In sickle cell disease (SCD), mutant hemoglobin S polymerizes when deoxygenated, driving red blood cell (RBC)-dependent vaso-occlusion and hemolysis. These processes lead to platelet and hemostatic activation, pulmonary hypertension (PH) and vascular disease. Transgenic-knockout sickle (BERK) mice that express exclusively human α- and βS-globins mimic SCD in humans by displaying reduced nitric oxide (NO) bioavailability, impaired NO-mediated vascular reactivity and PH. Recently, the platelet α-granule protein thrombospondin-1 (TSP1) was found to be elevated in the plasma of patients with SCD and to potently inhibit physiologic NO signaling, via binding to the cell surface receptor CD47. We hypothesized that blocking the TSP1-CD47 interaction may restore NO signaling and prevent PH in BERK mice. To test this hypothesis we conducted a transplantation experiment to explore the repopulating potential of BERK bone marrow (BM) in lethally myeloablated CD47KO recipients and the impact of the CD47 null milieu on the PH phenotype. We harvested the BM from 5–6 months old BERK mice and transplanted it into irradiated (10 Gy) 8–9 weeks old CD47KO mice (n=9). All recipients survived transplantation and were terminally evaluated 4 months post transplantation. Mice underwent blood sampling for determination of engraftment by hemoglobin electrophoresis, evaluation of endothelial dependent arterial vasodilation by myography, full pulmonary hemodynamic assessment and measurement of right ventricular hypertrophy (RVH) using the Fulton Index (ratio of ventricular weights (right ventricle/left ventricle including septum). The chimeras had 98.3% (SD 0.6%) hemoglobin S, thereby demonstrating full donor chimerism. Segments of thoracic aortas from the chimeras were mounted on a myograph system and exposed to acetylcholine, a physiologic vasodilator that stimulates endothelial nitric oxide synthase (eNOS) activation. Concentration-response curves showed that the arterial segments from chimeras that lacked tissue CD47 had improved endothelial-dependent vasodilation, as evaluated by % relaxation in response to acetylcholine, as compared to arterial segments from BERK mice (P < 0.05). Hemodynamic data showed that the tissue CD47KO chimeras had lower right ventricular end systolic pressure (RV ESP) as compared to BERK mice (22 vs. 31 mm Hg, p<0.05). Conversely, their RV ESP did not significantly differ from historical control C57BL/6 mice (22 vs. 20 mm Hg, NS, panel A). Measurement of RVH (Fulton Index) similarly revealed that the chimeras were protected from RVH (p<0.05, panel B). Thus, despite the presence of sickle RBC, the absence of the TSP1-CD47 signaling axis improved endothelial-eNOS-NO signaling and reduced pulmonary pressures and RVH responses. These data demonstrate that BM from BERK mice successfully engrafts CD47KO mice, and that in the absence of the TSP1-CD47 axis endothelial and vascular function improves and PH is ameliorated. We now plan to validate these results in controlled experiments where BM from BERK mice is transplanted in CD47KO and C57BL mice as controls. We expect that unlike C57BL mice transplanted with BERK BM, CD47KO mice will be protected from the vascular complications of SCD, including PH.Figurelegend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure.Figure. legend: CD47KO mice transplanted with BERK BM (chimeras) show improved hemodynamics (Panel A) and less right ventricular (RV) hypertrophy as measured by the Fulton Index as compared to BERK mice (Panel B). * = statistically significant, NS = non significant, RV ESP = right ventricle end systolic pressure. Disclosures: Isenberg: Vasculox, Inc.: Equity Ownership.

scholarly journals Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Mark T. Gladwin ◽  
Gregory J. Kato
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Iron Chelation ◽  
Cell Disease ◽  
Intravascular Hemolysis ◽  
Inflammatory Stress ◽  
Risk Of Death ◽  
Cardiopulmonary Complications

Abstract Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity.1,2 Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias. A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggest that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood.3–5 In conclusion, pulmonary hypertension is common in patients with hereditary hemolytic anemias and is associated with a high risk of death in patients with sickle cell disease. New therapies targeting this vasculopathy and aimed at normalizing the vasodilator:vasoconstrictor balance are discussed.

Hemolysis in Sickle Cell Mice Causes Pulmonary Hypertension Due to Global Impairment in Nitric Oxide Bioavailability.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 785-785
Author(s):  
Lewis L. Hsu ◽  
Hunter C. Champion ◽  
Sally A. Campbell-Lee ◽  
Trinity J. Bivalacqua ◽  
Elizabeth A. Manci ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Animal Model ◽  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
No Production ◽  
Cell Disease ◽  
Sickle Hemoglobin ◽  
Pulmonary Vasodilators

Abstract Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiological mechanisms by which sickle hemoglobin leads to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model of severe sickle cell disease. Using micro-cardiac catheterization we found that all mice expressing exclusively human sickle hemoglobin develop pulmonary hypertension. Recognizing that the NO pathways can have complex abnormalities in other conditions of pulmonary hypertension, the NO axis in sickle mice was assessed by multiple methods. From a mechanistic standpoint the mice exhibit profound pulmonary and systemic endothelial dysfunction and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors and endothelium-dependent pulmonary vasodilators, and enhanced responses to vaso-constrictors. However, endothelium-independent vasodilation in the 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 coupling (dimerization), increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Consistent with a functional rather than structural defect, light microscopy and computed tomography of the lungs revealed no plexogenic arterial remodeling, thrombi/emboli, or inflammation. Transplanting sickle marrow into wild-type mice conferred the same phenotype. Similar pathobiology was observed in a non-sickle mouse model of acute alloimmune hemolysis, supporting a major role of hemolysis as a mechanism for this dysregulation of NO and vasculopathy. In this study, alloimmune hemolytic mice were chosen for comparison in order to generalize beyond hemoglobinopathies. Future analogous studies with thalassemic mice may be useful to model pulmonary hypertension in human thalassemia intermedia. In conclusion, this animal model extends the evidence for global impairment in NO responsiveness and NO production in sickle cell disease, and suggests that hemolytic anemia is associated with endothelial dysfunction and pulmonary hypertension.

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