Non-hematopoietic deficiency of proprotein convertase subtilisin/kexin type 9 deficiency leads to more severe anemia in a murine model of sickle cell disease

Autor:	Yuqing Eugene Chen, Chiao Guo, Haocheng Lu, Daniel T. Eitzman, Juan Wang, Jessica Venugopal
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	Male 0301 basic medicine Reticulocytosis lcsh:Medicine Diseases 030204 cardiovascular system & hematology Mice chemistry.chemical_compound 0302 clinical medicine hemic and lymphatic diseases Subtilisins lcsh:Science Bone Marrow Transplantation education.field_of_study Multidisciplinary Serine Endopeptidases Anemia Hemolysis Cholesterol Liver Kexin lipids (amino acids peptides and proteins) Proprotein Convertases Proprotein Convertase 9 medicine.symptom congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Population Anemia Sickle Cell Article 03 medical and health sciences Medical research Internal medicine medicine Animals cardiovascular diseases education business.industry PCSK9 lcsh:R Cholesterol LDL medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Receptors LDL chemistry LDL receptor lcsh:Q business
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-7 (2020) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58f857dea55900c075235678e0424574 http://link.springer.com/article/10.1038/s41598-020-73463-9 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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