Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower
cholesterol and is associated with reduced vascular complications in the general population.
Cholesterol lowering may also have beneficial effects in
sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD.
Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9+/+, SCDbmt) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9-/-, SCDbmt), and SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt). Although
cholesterol levels were lower in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice,
anemia was more severe in Pcsk9-/-, SCDbmt mice. Increased
reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte
phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased
iron in Pcsk9-/-, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice consistent with greater
hemolysis. SCD mice with deficiency of LDLR (Ldlr-/-, SCDbmt mice) had similar
anemia as Ldlr+/+, SCDbmt mice despite higher serum
cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened
anemia in SCD mice due to increased
hemolysis. These findings may have implications for
lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of
anemia severity.