Abstract
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.
Highlights
Sickle cell disease (SCD) is one of the most common inherited blood disorders in humans with millions affected worldwide[1]
To generate a model of sickle cell disease (SCD) with low cholesterol levels, bone marrow was transplanted from SCD donor to Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficient or WT recipients to generate the experimental Pcsk9−/−, SCDbmt mice and Pcsk9+/+, SCDbmt controls
Serum levels of PCSK9 were undetectable in Pcsk9−/−, SCDbmt mice and within a normal range for Pcsk9+/+, SCDbmt mice confirming that circulating PCSK9 is derived from non-hematopoietic organs (Fig. 1A)
Summary
Sickle cell disease (SCD) is one of the most common inherited blood disorders in humans with millions affected worldwide[1]. Circulating lipids may play a role in erythrocyte membrane h omeostasis[7] It is unknown whether the observed decrease in circulating cholesterol in SCD patients potentiates or ameliorates negative SCD phenotypes, or if it is merely a byproduct of hemolysis-induced increase in erythropoiesis with no affect on SCD-related anemia or organ damage. Mouse models of SCD have been developed that mimic the predominant features of SCD in h umans[15,16,17] These mice exhibit hemolysis, anemia, splenomegaly, and multi-organ infarcts[15,16,17]. As PCSK9 is primarily produced in the liver, transplantation of SCD marrow into recipient mice should produce SCD mice with no circulating PCSK9 and hypocholesterolemia This model was implemented to determine if decreased circulating lipids was beneficial towards the anemia of SCD and related vascular phenotypes
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