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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 (<jats:italic>Pcsk9<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup>) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (<jats:italic>Pcsk9<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup>), and SCD mice with deficiency of LDLR (<jats:italic>Ldlr<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup>). Although cholesterol levels were lower in <jats:italic>Pcsk9<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice compared to <jats:italic>Pcsk9<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice, anemia was more severe in <jats:italic>Pcsk9<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in <jats:italic>Pcsk9<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice compared to <jats:italic>Pcsk9<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (<jats:italic>Ldlr<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> mice) had similar anemia as <jats:italic>Ldlr<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup>, SCD<jats:sup>bmt<\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41598-020-73463-9","type":"journal-article","created":{"date-parts":[[2020,10,5]],"date-time":"2020-10-05T10:05:05Z","timestamp":1601892305000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Non-hematopoietic deficiency of proprotein convertase subtilisin\/kexin type 9 deficiency leads to more severe anemia in a murine model of sickle cell disease"],"prefix":"10.1038","volume":"10","author":[{"given":"J.","family":"Venugopal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. 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