Hypoxia Response and Stroke Susceptibility with Sickle Cell Anemia (SCA)

Abstract

Individuals with SCA are susceptible to stroke at an early age. Since hypoxia is a hallmark of stroke, we hypothesize that hypoxic responses of some genes may differ constitutively in individuals at risk for sickle‐stroke. Blood outgrowth endothelial cells (BOEC) were isolated from African American donors without SCA (NS) as well as SCA donors at risk (AR) or not at risk (NAR) of early stroke. Risk was assessed as occlusive disease at the Circle of Willis. BOEC were incubated under hypoxic (0.5% O2) conditions and induction of 9 known hypoxia response genes were assessed by qRT‐PCR. Combined data from 30 min and 1h hypoxia, indicated significant differences (p<.05) between groups in fold induction of several genes: AR>NAR (Elk‐1, tPa, HIF1α, HIF1β and Endothelin‐1), AR>NS (ELK‐1, tPa), and NS>NAR (Elk‐1, HIF1α). Slightly significant differences (p<.1) included AR>NAR (Egr‐1, Flk‐1) and AR>NS (Flk‐1, Egr‐1, HIF1α, Endothelin‐1). Under normoxic conditions, most genes did not differ at p<.05 between groups. The 9 genes are known for complex impacts on inflammation, angiogenesis, apoptosis and cerebral ischemia. However, the high hypoxia response of AR compared to NAR BOEC suggests that AR individuals may lack protective mechanisms that NAR have. In conclusion, individuals with SCA at risk for stroke respond to hypoxia with exaggerated expression of several genes.Funding: NIH (HL076540 & HL55552)