Heparin Does Not Regulate Circulating Human PCSK9

BackgroundPCSK9 chaperones the hepatic low-density lipoprotein receptor (LDLR) for lysosomal degradation, elevating serum LDL cholesterol and increasing the risk of atherosclerotic heart disease. Though the major effect on the hepatic LDLR comes from secreted PCSK9, the details of PCSK9 reuptake into the hepatocyte remain unclear. In both tissue culture and animal models, heparan sulfate proteoglycans (HSPGs) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We hypothesized that if this PCSK9:HSPG interaction is important in humans, disrupting the interaction with unfractionated heparin (UFH) would acutely displace PCSK9 from the liver and increase plasma PCSK9. MethodsWe obtained remnant plasma samples from 160 subjects undergoing cardiac catheterization before and after administration of intravenous UFH. PCSK9 levels were determined using a commercial ELISA. ResultsMedian plasma PCSK9 concentrations were 113 ng/ml prior to UFH and 119 ng/ml afterwards. This difference was not significantly different (p = 0.83, 95% CI of difference: -6.23 to 6.31 ng/ml). Tests for equivalence provided 95% confidence that UFH administration would not raise PCSK9 levels by more than 4.7% of the baseline value. No predefined subgroups exhibited an effect of UFH on circulating PCSK9. ConclusionAdministration of UFH does not result in a clinically meaningful effect on circulating PCSK9 in humans. These results suggest that disruption of the PCSK9:HSPG interaction does not affect PCSK9 reuptake into the liver. Further, they cast doubt on the clinical utility of disrupting the PCSK9:HSPG interaction as a therapeutic strategy for PCSK9 inhibition. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/22279796v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f04518org.highwire.dtl.DTLVardef@48638eorg.highwire.dtl.DTLVardef@803104org.highwire.dtl.DTLVardef@12167c_HPS_FORMAT_FIGEXP M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIPrior tissue culture and animal data suggest that PCSK9 interacts with hepatic heparan sulfate proteoglycans to enter the liver and raise cholesterol levels C_LIO_LIWe found no evidence that heparin, a competitive inhibitor of heparan sulfate proteoglycans, acutely affects PCSK9 in humans C_LI What are the clinical implications?O_LIHeparin is unlikely to be successfully repurposed as a PCSK9 inhibitor C_LI