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Modulation of the Vascular Endothelial Inflammatory Response by Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9)
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A4748 - Modulation of the Vascular Endothelial Inflammatory Response by Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9)
Author Block: A. K. Leung1, G. Grzelkovski2, K. Roveran Genga1, J. A. Russell1, J. H. Boyd1, K. R. Walley1; 1Centre for Heart Lung Innovation, St. Paul's Hospital, The University of British Columbia, Vancouver, BC, Canada, 2Federal University of Parana, Curitiba, Brazil.
Rationale: Previously, we discovered that pathogen lipids carried within LDL are cleared from the circulation via hepatic LDL receptors (LDLR). Proprotein convertase subtilisin-kexin type 9 (PCSK9) down-regulates LDLR density on hepatocytes, hence PCSK9 function is negatively correlated with the hepatic clearance of pathogen lipids. In addition to hepatocytes, vascular endothelial cells also express targets of PCSK9 including LDLR, VLDLR, LRP1, LRP8 (APOER2) and CD36. Therefore we hypothesize that PCSK9 modulates the inflammatory response in vascular endothelial cells by regulating the internalization of pathogen lipids via targets of PCSK9.
Methods: We used Human Umbilical Vein Endothelial Cells (HUVEC, Lonza) as an in vitro model of pathogen lipid uptake and inflammatory response in vascular endothelial cells. Flow cytometry was used to measure the cellular uptake of fluorescently-labeled lipopolysaccharide (LPS) in response to exogenous recombinant PCSK9. Inflammatory cytokine levels in cell-free media were measured using enzyme-linked immunosorbent assay (ELISA) to monitor the inflammatory response in HUVEC following treatment with LPS and PCSK9.
Results: The cellular uptake of fluorescently-labeled LPS in HUVEC decreased in a dose-dependent manner with added PCSK9 as measured using flow cytometry. Consistent with the decreased cellular uptake of LPS, PCSK9 also decreased Interleukin-8 (IL-8) production. Blocking antibodies against the LDLR also induced a dose-dependent decrease in the uptake of LPS.
Conclusions: PCSK9 reduced the cellular uptake of LPS into vascular endothelial cells via the LDLR. This decrease in cellular uptake is correlated with a decrease in inflammatory response as measured by IL-8 levels. Our results suggest that strategies to improve hepatic clearance of pathogen lipids through PCSK9 inhibition may paradoxically enhance vascular endothelial inflammation.
This work is funded by the Canadian Institutes of Health Research (CIHR) and the Michael Smith Foundation for Health Research (MSFHR).
Author Block: A. K. Leung1, G. Grzelkovski2, K. Roveran Genga1, J. A. Russell1, J. H. Boyd1, K. R. Walley1; 1Centre for Heart Lung Innovation, St. Paul's Hospital, The University of British Columbia, Vancouver, BC, Canada, 2Federal University of Parana, Curitiba, Brazil.
Rationale: Previously, we discovered that pathogen lipids carried within LDL are cleared from the circulation via hepatic LDL receptors (LDLR). Proprotein convertase subtilisin-kexin type 9 (PCSK9) down-regulates LDLR density on hepatocytes, hence PCSK9 function is negatively correlated with the hepatic clearance of pathogen lipids. In addition to hepatocytes, vascular endothelial cells also express targets of PCSK9 including LDLR, VLDLR, LRP1, LRP8 (APOER2) and CD36. Therefore we hypothesize that PCSK9 modulates the inflammatory response in vascular endothelial cells by regulating the internalization of pathogen lipids via targets of PCSK9.
Methods: We used Human Umbilical Vein Endothelial Cells (HUVEC, Lonza) as an in vitro model of pathogen lipid uptake and inflammatory response in vascular endothelial cells. Flow cytometry was used to measure the cellular uptake of fluorescently-labeled lipopolysaccharide (LPS) in response to exogenous recombinant PCSK9. Inflammatory cytokine levels in cell-free media were measured using enzyme-linked immunosorbent assay (ELISA) to monitor the inflammatory response in HUVEC following treatment with LPS and PCSK9.
Results: The cellular uptake of fluorescently-labeled LPS in HUVEC decreased in a dose-dependent manner with added PCSK9 as measured using flow cytometry. Consistent with the decreased cellular uptake of LPS, PCSK9 also decreased Interleukin-8 (IL-8) production. Blocking antibodies against the LDLR also induced a dose-dependent decrease in the uptake of LPS.
Conclusions: PCSK9 reduced the cellular uptake of LPS into vascular endothelial cells via the LDLR. This decrease in cellular uptake is correlated with a decrease in inflammatory response as measured by IL-8 levels. Our results suggest that strategies to improve hepatic clearance of pathogen lipids through PCSK9 inhibition may paradoxically enhance vascular endothelial inflammation.
This work is funded by the Canadian Institutes of Health Research (CIHR) and the Michael Smith Foundation for Health Research (MSFHR).
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