Strategies to improve hemorheology and clinical outcome of sickle cell anemia patients by red blood cell derived nitric oxide

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In recent years we have shown that red blood cell nitric oxide synthase (RBC-NOS) produced nitric oxide (NO) is of particular importance to maintain and regulate RBC deformability. Part of this RBC-NOS derived NO is further oxidized to nitrite to function as NO reserve. Other part of the NO binds to RBC proteins, such as a- und ß-spectrin, thus promoting the stabilization of the RBC cyto-skeleton, which positively affects RBC deformability. Sickle cell anemia (SCA) patients show im-paired blood rheology characterized by a severe reduction in RBC deformability, a high rate of hemolysis and enhanced eryptosis. In collaboration with the research group of Prof. Philippe Connes we were able to show that, against expectation, NO production in RBC of SCA patients is increased compared to healthy controls. This is caused by higher activation of the Akt kinase pathway, which consequently increases RBC-NOS activation. The produced NO binds to proteins of the cytoskeleton, most likely a- und ß- spectrin but RBC deformability is still significantly reduced in these patients. To investigate this phenomenon and to develop strategies to improve hemorheology and to reduce clinical complications, we defined the following objectives for this project proposal: 1. Elucidation of hemorheological changes in SCA patients by in vivo investigations of the RBC-NOS and Akt signaling pathway: Relationship between hemorheology, RBC-NOS profile and clinical se-verity. 2. Improvement of RBC deformability and cell integrity, key factors of the known clinical complica-tions, through in vitro modulation of RBC-NOS dependent and independent NO production. Rela-tionship between RBC-NOS derived NO, oxidative/nitrosative stress and RBC deformability. 3. Improvement of RBC deformability and cell integrity by in vitro modulation of intra-erythrocytic NO content by applied shear stress: Pre-investigation of subsequent in vivo exercise intervention. 4. Improvement of NO formation in RBC with subsequent increase in RBC deformability by in vivo exercise intervention. 5. Effects of pharmacological increase in systemic NO content in murine SCA models under base-line conditions and during vaso-occlusive events.