Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice
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 inhi...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520337913 |
| _version_ | 1819297439683706880 |
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| author | Jean-Mathieu Berger Angel Loza Valdes Jesper Gromada Norma Anderson Jay D. Horton |
| author_facet | Jean-Mathieu Berger Angel Loza Valdes Jesper Gromada Norma Anderson Jay D. Horton |
| author_sort | Jean-Mathieu Berger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T05:14:02Z |
| format | Article |
| id | doaj.art-5c160248175a4c99956dc08904ce7b06 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T05:14:02Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-5c160248175a4c99956dc08904ce7b062022-12-21T17:13:36ZengElsevierJournal of Lipid Research0022-22752017-08-0158816611669Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in miceJean-Mathieu Berger0Angel Loza Valdes1Jesper Gromada2Norma Anderson3Jay D. Horton4Departments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TXDepartments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TXRegeneron Pharmaceuticals, Inc., Tarrytown, NYDepartments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TXTo whom correspondence should be addressed.; Departments of Internal Medicine and Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TXProprotein 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.http://www.sciencedirect.com/science/article/pii/S0022227520337913lipopolysaccharideendotoxemiacholesterolLDLPCSK9 |
| spellingShingle | Jean-Mathieu Berger Angel Loza Valdes Jesper Gromada Norma Anderson Jay D. Horton Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice Journal of Lipid Research lipopolysaccharide endotoxemia cholesterol LDL PCSK9 |
| title | Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice |
| title_full | Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice |
| title_fullStr | Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice |
| title_full_unstemmed | Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice |
| title_short | Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice |
| title_sort | inhibition of pcsk9 does not improve lipopolysaccharide induced mortality in mice |
| topic | lipopolysaccharide endotoxemia cholesterol LDL PCSK9 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520337913 |
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