PMID- 36475702
OWN - NLM
STAT- MEDLINE
DCOM- 20230127
LR  - 20240202
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 43
IP  - 2
DP  - 2023 Feb
TI  - Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase 
      Subtilisin-Kexin Type 9) in a General Population-Brief Report.
PG  - 352-358
LID - 10.1161/ATVBAHA.122.318556 [doi]
AB  - BACKGROUND: PCSK9 (proprotein convertase subtilisin-kexin type 9) chaperones the 
      hepatic LDLR (low-density lipoprotein receptor) for lysosomal degradation, 
      elevating serum LDL (low-density lipoprotein) cholesterol and promoting 
      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, HSPGs (heparan sulfate 
      proteoglycans) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We 
      hypothesized that if this PCSK9:HSPG interaction is important in humans, 
      disrupting it with unfractionated heparin (UFH) would acutely displace PCSK9 from 
      the liver and increase plasma PCSK9. METHODS: We obtained remnant plasma samples 
      from 160 subjects undergoing cardiac catheterization before and after 
      administration of intravenous UFH. PCSK9 levels were determined using a 
      commercial enzyme-linked immunosorbent assay. RESULTS: Median plasma PCSK9 was 
      113 ng/mL prior to UFH and 119 ng/mL afterward. This difference was not 
      significant (P=0.83 [95% CI, -6.23 to 6.31 ng/mL]). Equivalence testing provided 
      95% confidence that UFH would not raise plasma PCSK9 by > 4.7%. Among all 
      subgroups, only subjects with the lowest baseline PCSK9 concentrations exhibited 
      a response to UFH (8.8% increase, adj. P=0.044). A modest correlation was 
      observed between baseline plasma PCSK9 and the change in plasma PCSK9 due to UFH 
      (R(S)=-0.3634; P<0.0001). CONCLUSIONS: Administration of UFH does not result in a 
      clinically meaningful effect on circulating PCSK9 among an unselected population 
      of humans. The results cast doubt on the clinical utility of disrupting the 
      PCSK9:HSPG interaction as a general therapeutic strategy for PCSK9 inhibition. 
      However, the observations suggest that in selected populations, disrupting the 
      PCSK9:HSPG interaction could still affect PCSK9 reuptake and offer a therapeutic 
      benefit.
FAU - Xia, Vivian Q
AU  - Xia VQ
AD  - Division of Cardiology, Zuckerberg San Francisco General Hospital, CA (V.Q.X., 
      L.S.Z., J.S.M., J.S.C.).
AD  - Department of Medicine (V.Q.X., L.S.Z., J.S.M., J.S.C.), University of 
      California, San Francisco.
FAU - Ong, Chui Mei
AU  - Ong CM
AD  - Department of Laboratory Medicine (C.M.O., A.H.B.W.), University of California, 
      San Francisco.
AD  - Clinical Chemistry Laboratory, Zuckerberg San Francisco General Hospital, CA 
      (C.M.O., A.H.B.W.).
FAU - Zier, Lucas S
AU  - Zier LS
AD  - Division of Cardiology, Zuckerberg San Francisco General Hospital, CA (V.Q.X., 
      L.S.Z., J.S.M., J.S.C.).
AD  - Department of Medicine (V.Q.X., L.S.Z., J.S.M., J.S.C.), University of 
      California, San Francisco.
FAU - MacGregor, John S
AU  - MacGregor JS
AD  - Division of Cardiology, Zuckerberg San Francisco General Hospital, CA (V.Q.X., 
      L.S.Z., J.S.M., J.S.C.).
AD  - Department of Medicine (V.Q.X., L.S.Z., J.S.M., J.S.C.), University of 
      California, San Francisco.
FAU - Wu, Alan H B
AU  - Wu AHB
AD  - Department of Laboratory Medicine (C.M.O., A.H.B.W.), University of California, 
      San Francisco.
AD  - Clinical Chemistry Laboratory, Zuckerberg San Francisco General Hospital, CA 
      (C.M.O., A.H.B.W.).
FAU - Chorba, John S
AU  - Chorba JS
AUID- ORCID: 0000-0002-6397-6348
AD  - Division of Cardiology, Zuckerberg San Francisco General Hospital, CA (V.Q.X., 
      L.S.Z., J.S.M., J.S.C.).
AD  - Department of Medicine (V.Q.X., L.S.Z., J.S.M., J.S.C.), University of 
      California, San Francisco.
LA  - eng
GR  - K08 HL124068/HL/NHLBI NIH HHS/United States
GR  - R01 HL146404/HL/NHLBI NIH HHS/United States
GR  - R01 HL159457/HL/NHLBI NIH HHS/United States
GR  - R03 HL145259/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221208
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.21.- (Serine Endopeptidases)
RN  - EC 3.4.21.- (Proprotein Convertases)
RN  - 0 (Heparan Sulfate Proteoglycans)
RN  - 0 (Receptors, LDL)
RN  - 0 (Cholesterol, LDL)
RN  - EC 3.4.21.- (Subtilisins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Proprotein Convertase 9/metabolism
MH  - *Heparin
MH  - Serine Endopeptidases
MH  - Proprotein Convertases/metabolism
MH  - Heparan Sulfate Proteoglycans
MH  - Receptors, LDL/metabolism
MH  - Cholesterol, LDL
MH  - Subtilisins
PMC - PMC10038152
MID - NIHMS1854107
OTO - NOTNLM
OT  - cholesterol
OT  - heart disease
OT  - heparin
OT  - hepatocyte
OT  - lipoproteins
OT  - liver
OT  - translational research
EDAT- 2022/12/09 06:00
MHDA- 2023/01/28 06:00
PMCR- 2024/02/01
CRDT- 2022/12/08 09:48
PHST- 2022/12/09 06:00 [pubmed]
PHST- 2023/01/28 06:00 [medline]
PHST- 2022/12/08 09:48 [entrez]
PHST- 2024/02/01 00:00 [pmc-release]
AID - 10.1161/ATVBAHA.122.318556 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2023 Feb;43(2):352-358. doi: 
      10.1161/ATVBAHA.122.318556. Epub 2022 Dec 8.