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

Venugopal, Jessica; Wang, J; Guo, Chiao; Lü, Hong; Chen, Y E; Eitzman, Daniel T.

doi:10.1038/s41598-020-73463-9

Cited by 7 publications

(15 citation statements)

References 34 publications

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“…Erythrocytes in blood extracted from SCD humans or mice undergo ex vivo sickling, which may be reflective of the in vivo sickling tendency 36,37 . Consistent with the reduced haemolysis observed in vivo following anakinra treatment, erythrocyte sickling in whole blood was reduced in anakinra‐treated mice.…”

Section: Discussionmentioning

confidence: 53%

Interleukin‐1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet‐mediated erythrocyte sickling

et al. 2021

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Sickle cell disease (SCD) is associated with haemolytic anaemia and secondary activation of leucocytes and platelets, which in turn may further exacerbate haemolysis. As cytokine signalling pathways may participate in this cycle, the present study investigated whether pharmacological blockade of the interleukin-1 receptor (IL-1R) would mitigate anaemia in a murine model of SCD. Within 2 weeks of treatment, reduced markers of haemolysis were observed in anakinra-treated mice compared to vehicle-treated mice. After 4 weeks of anakinra treatment, mice showed increased numbers of erythrocytes, haemoglobin, and haematocrit, along with reduced reticulocytes. Blood from anakinra-treated mice was less susceptible to ex vivo erythrocyte sickling and was resistant to exogenous IL-1b-mediated sickling. Supernatant generated from IL-1b-treated platelets was sufficient to promote erythrocyte sickling, an effect not observed with platelet supernatant generated from IL-1R À/À mice. The sickling effect of IL-1b-treated platelet supernatant was inhibited by a transforming growth factor-b (TGFb) neutralising antibody, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, and superoxide scavengers, but replicated by recombinant TGF-b. In conclusion, pharmacological IL-1R antagonism leads to improved anaemia in a murine SCD model. IL-1b stimulation of platelets promotes erythrocyte sickling. This effect may be mediated by platelet-derived TGF-b-induced reactive oxygen species generation though erythrocyte NADPH oxidase.

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Section: Discussionmentioning

confidence: 53%

Interleukin‐1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet‐mediated erythrocyte sickling

et al. 2021

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“…BMP signi cantly decreased in PCSK9 −/−SCD erythrocytes To investigate mechanism(s) underlying the more severe anemia and hemolysis observed in SCD mice with and without PCSK9 de ciency [19] , erythrocytes collected from control SCD mice and PCSK9 de cient SCD mice underwent untargeted lipidomics analysis to test the hypothesis that PCSK9 may affect erythrocyte lipids. Of 543 lipid species analyzed, 11 lipid species were different between the 2 groups of mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Animals -Male C57BL/6J (Wildtype, Wt, stock # 000664), homozygous SCD mice (SCD, stock # 013071, Townes model) and PCSK9 −/− (stock # 005993) mice were purchased from Jackson Labs (Bar Harbor ME). Bone marrow was transplanted from SCD donor to PCSK9 de cient or WT recipient to generate the experimental PCSK9 −/− SCD bone marrow transplant (bmt) mice and the PCSK9 +/+ SCD bmt controls, as previously [19] . Lipidomics -Blood was drawn from the retro-orbital sinus of iso ourane-anesthetized mice (n = 3 per group) into 3.2% sodium citrate.…”

Section: Methodsmentioning

confidence: 99%

“…Other LDLR-independent effects of PCSK9 have been described including effects on lysosomal degradation of other receptors related to the LDLR [17,18] . Although lipid lowering may be bene cial in SCD patients, SCD mice de cient in PCSK9 were shown to have more severe anemia with increased hemolysis [19] , effects that were found to be independent of LDLR expression [19] .…”

Section: Introductionmentioning

confidence: 99%

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Amiodarone improves anemia in a murine model of sickle cell disease and is associated with increased erythrocyte bis(monoacylglycerol) phosphate

Venugopal

Wang

Guo

et al. 2022

Preprint

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Sickle cell disease (SCD) is with associated altered plasma and erythrocyte lipid profiles. In a previous study, SCD mice with deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) were observed to have more severe anemia and increased sickling compared to control SCD mice. Although PCSK9 affects circulating low density lipoprotein (LDL) by regulation of the LDL receptor, the effect of PCSK9 on anemia was independent of LDL receptor expression. In the current study, erythrocyte metabolomics were performed and revealed altered erythrocyte lipid species between SCD mice with and without PCSK9. Of particular interest, the late endosome-specific lipid bis(mono)acylglycerol phosphate (BMP) 44:12 was markedly decreased in erythrocytes from SCD mice deficient in PCSK9 mice relative to control SCD mice. Incubation of sickle erythrocytes with a neutralizing antibody to BMP increased erythrocyte sickling in vitro. In vitro treatment of SCD erythrocytes with amiodarone (1.5 uM) or medroxyprogesterone (6.75 uM), two pharmacologic compounds known to increase BMP, resulted in reduced erythrocyte sickling. Treatment of SCD mice with amiodarone (10 mg/kg) for 2 weeks resulted in increased BMP, improvement in anemia with reduced reticulocytosis, and decreased ex vivo sickling. In conclusion, severity of anemia in SCD is improved with amiodarone treatment, an effect which may be mediated through increased erythrocyte BMP.

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“…Since HAMP is a major regulator of iron homeostasis and its levels are linked to different forms of anaemias, 53 the positive correlation between PCSK9 and HAMP expression also at steady‐state could have clinical implications. In fact, a recent study in mice demonstrated that non‐hematopoietic anaemia, independent of LDLR expression, was more severe in Pcsk9 KO mice 54 . It is important to note that conventional PCSK enzymes FURIN, PCSK5, PCSK6 and PCSK7 have been demonstrated to directly process pro‐hepcidin, 55 whereas FURIN has been reported to process PCSK9 56 .…”

Section: Discussionmentioning

confidence: 99%

Proprotein convertase subtilisin/kexin type 9 regulates the production of acute‐phase reactants from the liver

Sanz

Saralahti

Pekkarinen

et al. 2021

Liver International

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Background & Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) controls blood cholesterol levels by fostering the LDL receptor (LDLR) degradation in hepatocytes. Additionally, PCSK9 has been suggested to participate in immunoregulation by modulating cytokine production. We studied the immunological role of PCSK9 in Streptococcus pneumoniae bacteraemia in vivo and in a human hepatocyte cell line. Methods CRISPR/Cas9 mutagenesis was utilized to create pcsk9 knock‐out (KO) zebrafish, which were infected with S pneumoniae to assess the role of PCSK9 for the survival of the fish and in the transcriptomic response of the liver. The direct effects of PCSK9 on the expression of acute‐phase reaction (APR) genes were studied in HepG2 cells. Results The pcsk9 KO zebrafish lines (pcsk9tpu‐13 and pcsk9tpu‐2,+15) did not show developmental defects or gross phenotypical differences. In the S pneumoniae infected zebrafish, the mortality of pcsk9 KOs was similar to the controls. A liver‐specific gene expression analysis revealed that a pneumococcal challenge upregulated pcsk9, and that the pcsk9 deletion reduced the expression of APR genes, including hepcidin antimicrobial peptide (hamp) and complement component 7b (c7b). Accordingly, silencing PCSK9 in vitro in HepG2 cells using small interfering RNAs (siRNAs) decreased HAMP expression. Conclusions We demonstrate that PCSK9 is not critical for zebrafish survival in a systemic pneumococcal infection. However, PCSK9 deficiency was associated with the lower expression of APR genes in zebrafish and altered the expression of innate immunity genes in a human hepatocyte cell line. Overall, our data suggest an evolutionarily conserved function for PCSK9 in APR in the liver.

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

Cited by 7 publications

References 34 publications

Interleukin‐1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet‐mediated erythrocyte sickling

Interleukin‐1 receptor antagonism leads to improved anaemia in a murine model of sickle cell disease and is associated with reduced ex vivo platelet‐mediated erythrocyte sickling

Amiodarone improves anemia in a murine model of sickle cell disease and is associated with increased erythrocyte bis(monoacylglycerol) phosphate

Proprotein convertase subtilisin/kexin type 9 regulates the production of acute‐phase reactants from the liver

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