Dietary ω-3 Fatty Acid Supplementation As a Potential New Therapy for Vasculopathy in Sickle Cell Disease: Proof of Concept in a Transgenic Mouse Model

Sickle cell disease (SCD) is a genetic red cell disorder characterized by hemolytic anemia in association with acute and chronic life-threatening clinical complications mainly related to inflammatory vasculopathy. Promising, but limited, human studies have shown potential therapeutic effects of ω-3 fatty acid supplementation in SCD. Here, we sought to compare the effects of 6 weeks ω-6 (soybean oil diet, SD) vs ω-3 (fish oil diet, FD) diet on vasculopathy in SCD mice (Hba^tm1(HBA)Tow Hbb^{tm2(HBG1,HBB*)Tow}). We treated SCD and control healthy mice (AA, Hba^tm1(HBA)Tow Hbb^{tm3(HBG1,HBB)Tow}) (n=6-7 animals in each group). In SCD mice, FD was associated with a decreased the ratio of ω-6 to ω-3 fatty acids in red cell membranes, as well as a decrease in neutrophil count compared to SD. We then evaluated the effects of FD on cardiovascular system of SCD mice. We found that FD resulted in significantly (i) lower diastolic blood pressure; (ii) reduced cardiac output; (iii) down-regulation of VCAM-1, ET-1 and HO-1 expression in isolated aorta compared to SD, reaching levels similar to those observed in AA mice. In the lung of SCD mice, FD significantly reduced ET-1 expression compared to SD. FD was also associated with reduced bronchoalveolar lavage leukocyte and protein contents compared to SD, suggesting protection against pulmonary leak. We then studied the effect of FD during vaso-occusive crises (VOCs), mimicked by exposing SCD mice to hypoxia/reoxygenation (H/R) stress. In SCD mice, FD significantly (i) ameliorated the H/R-induced reduction in hematocrit and hemoglobin levels; (ii) reduced the fraction of dense red cells and the H/R-induced increase in neutrophil count. Histologic analysis revealed that H/R stress recapitulates the SCD acute organ damage. In the lung of H/R SCD mice, FD reduced inflammatory cell infiltrates, bronchial mucus, thrombosis, and ET-1 and ET1-1R expression. In isolated aorta from SCD mice exposed to H/R, FD prevented the H/R-induced ET-1 and VCAM-1 expression and the H/R-induced up-regulation of anti-oxidant systems compared to SD. These findings provide new insight into the mechanism of action of ω-3 supplementation on the pathogenesis of SCD and strengthen the rationale for ω-3 dietary supplementation as a simple therapeutic intervention to reduce vascular dysfunction in SCD.