D-4F Restores eNOS-Dependent Vasodilation in Sickle Cell Disease by Decreasing Proinflammatory HDL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2324-2324
Author(s):  
Kirkwood A. Pritchard ◽  
Jingli Wang ◽  
Hao Xu ◽  
Deron W. Jones ◽  
Sandra L. Holzhauer ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Sickle Cell Disease ◽  
Total Cholesterol ◽  
Sickle Cell ◽  
Critical Role ◽  
Chow Diet ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Hdl Function

Abstract Background: Vasoregulation is impaired in human and murine sickle cell disease (SCD). Chronic inflammation and oxidative stress impair vasodilation. High-density lipoprotein (HDL) plays an important role in attenuating inflammatory responses. Previously we showed 4F, an apoA-I mimetic designed to improve HDL function, dramatically restores vasodilation in SCD mice. Here, we examine mechanisms by which D-4F restores vasodilation in SCD mice and in mice made to develop SCD via fetal liver hematopoietic stem cell transplantation (HSCT). Effects of proinflammatory lipids and D-4F were determined in HSCT-SCD- LDL receptor null (Ldlr−/−) mice fed either chow or western diet (WD). The role of HDL was examined in HSCT-SCD-apoA-I null (apoA-I−/−) mice. Finally, the role of eNOS was examined in HSCT-SCD-eNOS deficient (eNOS−/−) mice. Mice were treated with or without D-4F (1mg/kg/d for 6–8 wks). Results: Total cholesterol concentrations in HSCT-SCD-Ldlr−/− mice fed lab chow were slightly increased compared to transgenic SCD mice (40–60 vs. 90–130 mg/dL, p<0.05) with no change in HDL. Acetylcholine-mediated vasodilation (Ach, 10-7 to 10-4M) in HSCT-SCD-Ldlr−/− mice was impaired compared to untreated non-SCD Ldlr−/− mice (10 vs 43%, p<0.05). D-4F restored eNOS-dependent vasodilation in HSCT-SCD-Ldlr−/− mice to the level in non-SCD Ldlr−/− mice. D-4F did not alter total cholesterol or HDL in HSCT-SCD-Ldlr−/− mice but did decrease proinflammatory HDL (580 vs 380, p<0.05), an index of oxidizability. In contrast to HSCT-SCD-Ldlr−/− mice fed chow diet, HSCT-SCD-Ldlr−/− mice fed WD had little to no ACh vasodilation (0–3%). D-4F increased vasodilation slightly in HSCT-SCD-Ldlr−/− fed WD (~12%). Total cholesterol and HDL increased in response to WD in HSCT-SCD-Ldlr−/− mice (p<0.01). D-4F induced minimal changes in total cholesterol, HDL or proinflammatory HDL in these mice. To examine the role of HDL, we found that vasodilation in HSCT-SCD-apoA-I−/− mice was reduced to ~25% compared to 65% in C57BL/6 mice (p<0.01). D-4F nearly doubled vasodilation to ~43% in HSCT-SCD-apoA-I−/− mice (p<0.05). L-NAME (100μM) blocked vasodilation in all HSCT-SCD-apoA-I−/− mice, indicating vasodilation was mediated exclusively by eNOS. In contrast, when we examined the effect of eNOS deficiency, ACh induced minimal increases in vasodilation (~22%). Dissection of cellular mechanisms mediating vasodilation revealed that a small portion HSCT-SCD-eNOS−/− mice was inhibited by L-NAME (i.e., NOS, ~12%), with none mediated by COX-prostacyclin (0%) and a small portion mediated by cytochrome P450 (~10%). Inhibitor studies revealed D-4F restored vasodilation in HSCT-SCD-eNOS−/− mice to ~52% (p<0.05) by predominately a L-NAME-inhibitable mechanism (NOS = 40%; COX-prostacylcin = 0% and cytochrome P450 = 11%). Conclusions: D-4F improves eNOS-dependent vasodilation even when hypercholesterolemia is superimposed on SCD. Measurements of proinflammatory HDL reveal D-4F restores vasodilation by protecting HDL against oxidation. Interestingly, D-4F protects vasodilation even in mice that have low levels of apoA-I-deficient HDL. Taken together, these data indicate proinflammatory HDL plays a critical role in mechanisms by which SCD impairs eNOS-dependent vasodilation and D-4F increases vasodilation, at least in part, by decreasing proinflammatory HDL in SCD.

scholarly journals Critical role of C5a in sickle cell disease

2019 ◽  
Vol 94 (3) ◽  
pp. 327-337 ◽  
Author(s):  
Gregory M. Vercellotti ◽  
Agustin P. Dalmasso ◽  
Terry R. Schaid ◽  
Julia Nguyen ◽  
Chunsheng Chen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Critical Role ◽  
Cell Disease

scholarly journals The Role of RBC Oxidative Stress in Sickle Cell Disease: From the Molecular Basis to Pathologic Implications

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1608
Author(s):  
Qinhong Wang ◽  
Rahima Zennadi
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Redox State ◽  
Continuous Production ◽  
Globin Gene ◽  
Critical Role ◽  
Cell Disease ◽  
Membrane Structure And Function

Sickle cell disease (SCD) is an inherited monogenic disorder and the most common severe hemoglobinopathy in the world. SCD is characterized by a point mutation in the β-globin gene, which results in hemoglobin (Hb) S production, leading to a variety of mechanistic and phenotypic changes within the sickle red blood cell (RBC). In SCD, the sickle RBCs are the root cause of the disease and they are a primary source of oxidative stress since sickle RBC redox state is compromised due to an imbalance between prooxidants and antioxidants. This imbalance in redox state is a result of a continuous production of reactive oxygen species (ROS) within the sickle RBC caused by the constant endogenous Hb autoxidation and NADPH oxidase activation, as well as by a deficiency in the antioxidant defense system. Accumulation of non-neutralized ROS within the sickle RBCs affects RBC membrane structure and function, leading to membrane integrity deficiency, low deformability, phosphatidylserine exposure, and release of micro-vesicles. These oxidative stress-associated RBC phenotypic modifications consequently evoke a myriad of physiological changes involved in multi-system manifestations. Thus, RBC oxidative stress in SCD can ultimately instigate major processes involved in organ damage. The critical role of the sickle RBC ROS production and its regulation in SCD pathophysiology are discussed here.

scholarly journals The Role of Hematopoietic Stem Cell Transplantation in the treatment of Sickle Cell Disease

2020 ◽  
Vol 7 (09) ◽  
pp. 5024-5032
Author(s):  
Carolina Wishner ◽  
Colleen Taylor ◽  
Monica Williams ◽  
Derian Kuneman
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Organ Damage ◽  
Cell Transplant ◽  
Cell Disease ◽  
Hematopoietic Stem

Abstract   Sickle cell disease (SCD) affects millions of people around the world and is associated with significant morbidity and premature mortality. It is a chronic, life-long illness that affects virtually every tissue in the body, worsens over time, with varying degrees of morbidity in everyone with the disease.  Before hematopoietic stem cell transplant (HCST), the mainstay of the management of SCD included early identification of the disease through newborn screening, infection prophylaxis with vaccinations and antibiotics, management of pain crises, blood transfusions, and hydroxyurea.   These treatments although beneficial, do not cure SCD, stop the progressive end-organ damage associated with this disease, and are lifelong.   Hematopoietic stem cell transplant is one of two treatment options that offer a cure for SCD and stops the progressive end-organ damage. The purpose of this article is to examine traditional treatments (best medical practice) and HCST for SCD and their associated complications.  The role of HCST in the treatment of sickle cell disease, as well as recent research on HSCT as a cure for SCD, risk factors, patient selection, limitations, and future use of this treatment option, are also reviewed.  Major issues surrounding the use of HCST for treating SCD include the optimal age for transplantation, disease severity, donor source, and the conditioning regimen before transplantation. The future of HCST including gene therapy is also discussed.

scholarly journals Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

2019 ◽  
Vol 8 (10) ◽  
pp. 1690 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Christopher Denton ◽  
Patjanaporn Chalacheva ◽  
Michael Khoo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Critical Role ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

scholarly journals Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease

2021 ◽  
Vol 22 (12) ◽  
pp. 6408
Author(s):  
Rani Ashouri ◽  
Madison Fangman ◽  
Alicia Burris ◽  
Miriam O. Ezenwa ◽  
Diana J. Wilkie ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Critical Role ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Cell Disease ◽  
Dynamic Activity ◽  
Free Heme

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.

Hemoglobinopathies

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 14-39 ◽  
Author(s):  
George F. Atweh ◽  
Joseph DeSimone ◽  
Yogen Saunthararajah ◽  
Hassana Fathallah ◽  
Rona S. Weinberg ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Experimental Models ◽  
Adult Patients ◽  
Main Theme ◽  
Cell Disease ◽  
Hematopoietic Stem

Abstract The outlook for patients with sickle cell disease has improved steadily during the last two decades. In spite of these improvements, curative therapies are currently available only to a small minority of patients. The main theme of this chapter is to describe new therapeutic options that are at different stages of development that might result in further improvements in the outlook for patients with these disorders. Dr. Joseph DeSimone and his colleagues had previously made the important observation that the hypomethylating agent 5-azacytidine can reverse the switch from adult to fetal hemoglobin in adult baboons. Although similar activity was demonstrated in patients with sickle cell disease and β-thalassemia, concern about the toxicity of 5-azacytidine prevented its widespread use in these disorders. In Section I, Dr. DeSimone discusses the role of DNA methylation in globin gene regulation and describe recent clinical experience with decitabine (an analogue of 5-azacytidine) in patients with sickle cell disease. These encouraging studies demonstrate significant fetal hemoglobin inducing activity of decitabine in patients who fail to respond to hydroxyurea. In Section II, Dr. George Atweh continues the same theme by describing recent progress in the study of butyrate, another inducer of fetal hemoglobin, in patients with sickle cell disease and β-thalassemia. The main focus of his section is on the use of a combination of butyrate and hydroxyurea to achieve higher levels of fetal hemoglobin that might be necessary for complete amelioration of the clinical manifestations of these disorders. Dr. Atweh also describes novel laboratory studies that shed new light on the mechanisms of fetal hemoglobin induction by butyrate. In Section III, Dr. Ronald Nagel discusses the different available transgenic sickle mice as experimental models for human sickle cell disease. These experimental models have already had a significant impact on our understanding of the pathophysiology of sickle cell disease. Dr. Nagel describes more recent studies in which transgenic sickle mice provide the first proof of principle that globin gene transfer into hematopoietic stem cells inhibits in vivo sickling and ameliorates the severity of the disease. Although stroke in adult patients with sickle cell disease is not as common as in children, adult hematologists, like their pediatric colleagues, need to make management decisions in adult patients with a stroke or a history of stroke. Dr. Robert Adams has led several large clinical studies that investigated the role of transfusions in the prevention of stroke in children with sickle cell disease. Much less is known, however, about the prevention of first or subsequent strokes in adult patients with sickle cell disease. In Section IV, Dr. Adams provides some general guidelines for the management of adult patients with stroke while carefully distinguishing between recommendations that are evidence-based and those that are anecdotal in nature.

scholarly journals Antiphospholipid Antibodies in Sickle Cell Disease: A Systematic Review and Exploratory Meta-Analysis

2021 ◽  
Vol 27 ◽  
pp. 107602962110029
Author(s):  
Mira Merashli ◽  
Alessia Arcaro ◽  
Maria Graf ◽  
Matilde Caruso ◽  
Paul R. J. Ames ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Antiphospholipid Antibodies ◽  
Meta Analysis ◽  
Age Groups ◽  
Anticardiolipin Antibodies ◽  
Cell Disease ◽  
Pooled Prevalence ◽  
The Relationship

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

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