Local effects of human PCSK9 on the atherosclerotic lesion

Ilaria Giunzioni, Hagai Tavori, Roman Covarrubias, Amy S. Major, Lei Ding, Youmin Zhang, Rachel M. Devay, Liang Hong, Daping Fan, Irene M. Predazzi, Shirya Rashid, Macrae F. Linton, Sergio Fazio

    Research output: Contribution to journalArticle

    58 Citations (Scopus)

    Abstract

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE-/- and LDLR-/- mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE-/- recipient mice, while increasing the infiltration of Ly6Chi inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6Chi-positive cell numbers in spleens of apoE-/- mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers TNF and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR-/- recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.

    Original languageEnglish (US)
    Pages (from-to)52-62
    Number of pages11
    JournalJournal of Pathology
    Volume238
    Issue number1
    DOIs
    StatePublished - Jan 1 2016

    Fingerprint

    LDL Receptors
    Macrophages
    Bone Marrow
    Apolipoproteins E
    Transgenic Mice
    Atherosclerosis
    Spleen
    Cholesterol
    Low Density Lipoprotein Receptor-Related Protein-1
    Inflammation
    Proprotein Convertase 9
    human PCSK9 protein
    Peritoneal Macrophages
    High Fat Diet
    Serum
    LDL Lipoproteins
    Interleukin-10
    LDL Cholesterol
    Blood Vessels
    Monocytes

    Keywords

    • atherosclerotic lesion
    • inflammation
    • LDLR
    • macrophages
    • mouse models
    • PCSK9

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine

    Cite this

    Giunzioni, I., Tavori, H., Covarrubias, R., Major, A. S., Ding, L., Zhang, Y., ... Fazio, S. (2016). Local effects of human PCSK9 on the atherosclerotic lesion. Journal of Pathology, 238(1), 52-62. https://doi.org/10.1002/path.4630

    Local effects of human PCSK9 on the atherosclerotic lesion. / Giunzioni, Ilaria; Tavori, Hagai; Covarrubias, Roman; Major, Amy S.; Ding, Lei; Zhang, Youmin; Devay, Rachel M.; Hong, Liang; Fan, Daping; Predazzi, Irene M.; Rashid, Shirya; Linton, Macrae F.; Fazio, Sergio.

    In: Journal of Pathology, Vol. 238, No. 1, 01.01.2016, p. 52-62.

    Research output: Contribution to journalArticle

    Giunzioni, I, Tavori, H, Covarrubias, R, Major, AS, Ding, L, Zhang, Y, Devay, RM, Hong, L, Fan, D, Predazzi, IM, Rashid, S, Linton, MF & Fazio, S 2016, 'Local effects of human PCSK9 on the atherosclerotic lesion', Journal of Pathology, vol. 238, no. 1, pp. 52-62. https://doi.org/10.1002/path.4630
    Giunzioni I, Tavori H, Covarrubias R, Major AS, Ding L, Zhang Y et al. Local effects of human PCSK9 on the atherosclerotic lesion. Journal of Pathology. 2016 Jan 1;238(1):52-62. https://doi.org/10.1002/path.4630
    Giunzioni, Ilaria ; Tavori, Hagai ; Covarrubias, Roman ; Major, Amy S. ; Ding, Lei ; Zhang, Youmin ; Devay, Rachel M. ; Hong, Liang ; Fan, Daping ; Predazzi, Irene M. ; Rashid, Shirya ; Linton, Macrae F. ; Fazio, Sergio. / Local effects of human PCSK9 on the atherosclerotic lesion. In: Journal of Pathology. 2016 ; Vol. 238, No. 1. pp. 52-62.
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