Andrew Barazia, Jing Li, Kyungho Kim, Namrata Shabrani, and Jaehyung Cho*
1 Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, United States
* Corresponding author : Jaehyung Cho
Abstract
Heterotypic cell-cell adhesion and aggregation mediate vaso-occlusive events in patients with sickle cell disease (SCD). Although hydroxyurea (HU), an inducer of fetal hemoglobin, is the main therapy for treatment of SCD, it is unclear whether it has immediate benefits on acute vaso-occlusive events in SCD patients. Using real-time fluorescence intravital microscopy, we demonstrated that short-term co-administration of HU and Akti XII, an AKT2 inhibitor, efficiently reduced neutrophil adhesion and platelet-neutrophil aggregation in venules of TNF-α- or hypoxia/reoxygenation-challenged Berkeley (SCD) mice. Importantly, compared with HU or Akti XII treatment alone, short-term treatment with both agents significantly improved survival in those mice. We found that the level of plasma nitric oxide species was elevated by HU but not Akti XII, AKT2 phosphorylation levels in activated neutrophils and platelets were reduced by Akti XII but not HU, and the expression of endothelial E-selectin and intercellular adhesion molecule 1 was decreased by either agent. Our results suggest that short-term co-administration of HU and Akti XII has immediate benefits on acute vaso-occlusive events and survival in SCD mice exceeding those seen for single therapy.