Biology of proprotein convertase subtilisin kexin 9: Beyond low-density lipoprotein cholesterol lowering

Giuseppe Danilo Norata, Hagai Tavori, Angela Pirillo, Sergio Fazio, Alberico L. Catapano

    Research output: Research - peer-reviewReview article

    • 10 Citations

    Abstract

    Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.

    LanguageEnglish (US)
    Pages429-442
    Number of pages14
    JournalCardiovascular Research
    Volume112
    Issue number1
    DOIs
    StatePublished - Oct 1 2016

    Fingerprint

    Proprotein Convertases
    Subtilisin
    LDL Cholesterol
    Hypercholesterolemia
    Cardiovascular Diseases
    LDL Receptors
    Virus Diseases
    Blood Vessels
    Immunity
    Sepsis
    Pharmacology
    Apoptosis
    Kidney
    Mutation
    Liver
    Brain
    Pharmaceutical Preparations
    Genes
    Therapeutics

    Keywords

    • APO B
    • LDL
    • LDLR
    • Monoclonal antibodies
    • PCSK9

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Cite this

    Biology of proprotein convertase subtilisin kexin 9 : Beyond low-density lipoprotein cholesterol lowering. / Norata, Giuseppe Danilo; Tavori, Hagai; Pirillo, Angela; Fazio, Sergio; Catapano, Alberico L.

    In: Cardiovascular Research, Vol. 112, No. 1, 01.10.2016, p. 429-442.

    Research output: Research - peer-reviewReview article

    Norata, Giuseppe Danilo ; Tavori, Hagai ; Pirillo, Angela ; Fazio, Sergio ; Catapano, Alberico L./ Biology of proprotein convertase subtilisin kexin 9 : Beyond low-density lipoprotein cholesterol lowering. In: Cardiovascular Research. 2016 ; Vol. 112, No. 1. pp. 429-442
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    abstract = "Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.",
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