Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice
| Autor: | Angel Loza Valdes, Norma N. Anderson, J.-M. Berger, Jay D. Horton, Jesper Gromada |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Lipopolysaccharides medicine.medical_specialty Lipopolysaccharide Inflammation QD415-436 Antibodies Monoclonal Humanized Biochemistry LDL Sepsis Cohort Studies PCSK9 03 medical and health sciences chemistry.chemical_compound Mice Endocrinology Internal medicine medicine Animals Humans Protease Inhibitors Research Articles Cholesterol business.industry endotoxemia PCSK9 Inhibitors lipopolysaccharide Antibodies Monoclonal cholesterol Cell Biology Cholesterol LDL medicine.disease Survival Analysis 3. Good health 030104 developmental biology chemistry LDL receptor Knockout mouse lipids (amino acids peptides and proteins) medicine.symptom business |
| Zdroj: | Journal of Lipid Research Journal of Lipid Research, Vol 58, Iss 8, Pp 1661-1669 (2017) |
| ISSN: | 1539-7262 |
| Popis: | Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that targets LDL receptors (LDLRs) for degradation in liver. Blocking the interaction of PCSK9 with the LDLR potently reduces plasma LDL cholesterol levels and cardiovascular events. Recently, it has been suggested that inhibition of PCSK9 might also improve outcomes in mice and humans with sepsis, possibly by increasing LDLR-mediated clearance of endotoxins. Sepsis is a complication of a severe microbial infection that has shared pathways with lipid metabolism. Here, we tested whether anti-PCSK9 antibodies prevent death from lipopolysaccharide (LPS)-induced endotoxemia. Mice were administered PCSK9 antibodies prior to, or shortly after, injecting LPS. In both scenarios, the administration of PCSK9 antibodies did not alter endotoxemia-induced mortality. Afterward, we determined whether the complete absence of PCSK9 improved endotoxemia-induced mortality in mice with the germ-line deletion of Pcsk9. Similarly, PCSK9 knockout mice were not protected from LPS-induced death. To determine whether low LDLR expression increased LPS-induced mortality, Ldlr−/− mice and PCSK9 transgenic mice were studied after injection of LPS. Endotoxemia-induced mortality was not altered in either mouse model. In a human cohort, we observed no correlation between plasma inflammation markers with total cholesterol levels, LDL cholesterol, and PCSK9. Combined, our data demonstrate that PCSK9 inhibition provides no protection from LPS-induced mortality in mice. |
| Databáze: | OpenAIRE |
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