Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 11/2004; 114(8):1136-45. DOI: 10.1172/JCI21633
Source: PubMed


In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with <1% gamma-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.

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    • "Currently, hydroxycarbamide or hydroxyurea (HU) is the only disease-modifying therapy approved for SCD, wherein the increased synthesis of Hb Fetal (HbF) is the main effect of this drug [98]. The augmented Hb F expression reduces several oxidative stress biomarkers and NO scavenging both in sickle cell mice and SCD patients [58] [86] [99] [100]. Other results also showed that increasing concentrations of Hb F, a protective effect of HU, is directly proportional to the increase in CAT activity and GSH levels, and decreased lipid peroxidation [58] [99]. "
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    ABSTRACT: Erythrocytes have an environment of continuous prooxidant generation due to hemoglobin (Hb) presence that represents an additional and quantitatively significant source of superoxide (O2(•-)) generation in biological systems. In order to counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Therefore, red blood cells (RBCs) uniquely function to protect Hb via a selective barrier allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. HbS molecules suffer repeated polymerization/depolymerization generating greater extent of reactive oxygen species (ROS), which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of prooxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute valuable means for preventing or delaying the development of organ complications.
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    • "et al 2006) A major risk factor for the development of PH is chronic haemolytic anaemia. Despite the robust basic and epidemiological data suggesting that an increased TRV is common and associated with high mortality in patients with SCD (Ataga, et al 2006, Dasgupta, et al 2010, De Castro, et al 2008, Frei, et al 2008, Gladwin, et al 2004, Hill, et al 2010, Hsu, et al 2007, Kato, et al 2006, Kaul, et al 2004, Machado, et al 2006, Meyer, et al 2010, Minniti, et al 2009, Naoman, et al 2009, Nolan, et al 2006, Nolan, et al 2005, Onyekwere, et al 2008, Reiter, et al 2002, Voskaridou, et al 2007, Yeo, et al 2007, Yeo, et al 2009), the importance of this complication and the mechanistic link to haemolytic anaemia has been recently challenged.(Bunn, et al, 2010) In order to further test our data-driven hypothesis we obtained frozen plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD), for analysis of a biomarker, NT-proBNP, which is elevated in the setting of pulmonary arterial and venous hypertension or left-sided heart disease. "
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    • "Finally, increased HbF content in sickle red cells prolongs red cell survival (Franco et al, 2006). The attendant reduction in haemolysis is likely to improve microvascular function and reduce chronic organ damage (Kaul et al, 2004). "
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