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J Clin Lipidol. 2018 Jul - Aug;12(4):1027-1038. doi: 10.1016/j.jacl.2018.03.092. Epub 2018 Apr 3.

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics.

Author information

1
Institut de Recherches Cliniques de Montréal (affiliated to the Université de Montréal), Montréal, Québec, Canada. Electronic address: marie-soleil.gauthier@ircm.qc.ca.
2
King Abdulaziz University, Jeddah, Saudi Arabia; McGill University, Montréal, Québec, Canada.
3
Institut de Recherches Cliniques de Montréal (affiliated to the Université de Montréal), Montréal, Québec, Canada.
4
General Surgery Department, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada.
5
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Department of Cardiology, McGill University, Montréal, Québec, Canada.
7
Institut de Recherches Cliniques de Montréal (affiliated to the Université de Montréal), Montréal, Québec, Canada; Department of Biochemistry, Université de Montréal, Montréal, Québec, Canada. Electronic address: benoit.coulombe@ircm.qc.ca.

Abstract

BACKGROUND:

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms.

OBJECTIVE:

To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels.

METHODS:

PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry.

RESULTS:

Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05).

CONCLUSIONS:

These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.

KEYWORDS:

Bariatric surgery; Cardiometabolic diseases; LDL cholesterol; Mass spectrometry; PCSK9; Phosphorylation; Posttranslational modifications; Quantitative proteomics; Statin; Triglycerides

PMID:
29699916
DOI:
10.1016/j.jacl.2018.03.092
[Indexed for MEDLINE]

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