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Research ArticleInflammation, Immunopharmacology, and Asthma

Apolipoprotein A-I (ApoA-I) Mimetic Peptide P2a by Restoring Cholesterol Esterification Unmasks ApoA-I Anti-Inflammatory Endogenous Activity In Vivo

Mariarosaria Bucci, Luisa Cigliano, Valentina Vellecco, Luca Domenico D'Andrea, Barbara Ziaco, Antonietta Rossi, Lidia Sautebin, Alessandro Carlucci, Paolo Abrescia, Carlo Pedone, Angela Ianaro and Giuseppe Cirino
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 716-722; DOI: https://doi.org/10.1124/jpet.111.189308
Mariarosaria Bucci
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Luisa Cigliano
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Valentina Vellecco
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Luca Domenico D'Andrea
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Barbara Ziaco
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Antonietta Rossi
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Lidia Sautebin
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Alessandro Carlucci
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Paolo Abrescia
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Carlo Pedone
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Angela Ianaro
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Giuseppe Cirino
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Abstract

The acute-phase protein haptoglobin (Hpt) binds apolipoprotein A-I (ApoA-I) and impairs its action on lecithin-cholesterol acyltransferase, an enzyme that plays a key role in reverse cholesterol transport. We have previously shown that an ApoA-I mimetic peptide, P2a, displaces Hpt from ApoA-I, restoring the enzyme activity in vitro. The aim of this study was to evaluate whether P2a displaces Hpt from ApoA-I in vivo and whether this event leads to anti-inflammatory activity. Mice received subplantar injections of carrageenan. Paw volume was measured before the injection and 2, 4, 6, 24, 48, 72, and 96 h thereafter. At the same time points, concentrations of HDL cholesterol (C) and cholesterol esters (CEs) were measured by high-performance liquid chromatography, and Hpt and ApoA-I plasma levels were evaluated by enzyme-linked immunosorbent assay. Western blotting analysis for nitric-oxide synthase and cyclooxygenase (COX) isoforms was also performed on paw homogenates. CEs significantly decreased in carrageenan-treated mice during edema development and negatively correlated with the Hpt/ApoA-I ratio. P2a administration significantly restored the CE/C ratio. In addition, P2a displayed an anti-inflammatory effect on the late phase of edema with a significant reduction in COX2 expression coupled to an inhibition of prostaglandin E2 synthesis, implying that, in the presence of P2a, CE/C ratio rescue and edema inhibition were strictly related. In conclusion, the P2a effect is due to its binding to Hpt with consequent displacement of ApoA-I that exerts anti-inflammatory activity. Therefore, it is feasible to design drugs that, by enhancing the physiological endogenous protective role of ApoA-I, may be useful in inflammation-based diseases.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.189308.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    C
    cholesterol
    RCT
    reverse cholesterol transport
    HDL
    high-density lipoprotein
    ApoA-I
    apolipoprotein A-I
    LCAT
    lecithin-cholesterol acyltransferase
    Hpt
    haptoglobin
    CE
    cholesteryl ester
    BSA
    bovine serum albumin
    COX
    cyclooxygenase
    iNOS
    inducible nitric-oxide synthase
    PGE2
    prostaglandin E2
    P2as
    scramble peptide
    HPLC
    high-performance liquid chromatography
    ELISA
    enzyme-linked immunosorbent assay
    HDL-C
    unesterified and total cholesterol
    eNOS
    endothelial nitric-oxide synthase.

  • Received October 24, 2011.
  • Accepted December 12, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

ApoA-I Mimetic Peptide P2a Anti-Inflammatory Agent

Mariarosaria Bucci, Luisa Cigliano, Valentina Vellecco, Luca Domenico D'Andrea, Barbara Ziaco, Antonietta Rossi, Lidia Sautebin, Alessandro Carlucci, Paolo Abrescia, Carlo Pedone, Angela Ianaro and Giuseppe Cirino
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 716-722; DOI: https://doi.org/10.1124/jpet.111.189308

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Research ArticleInflammation, Immunopharmacology, and Asthma

ApoA-I Mimetic Peptide P2a Anti-Inflammatory Agent

Mariarosaria Bucci, Luisa Cigliano, Valentina Vellecco, Luca Domenico D'Andrea, Barbara Ziaco, Antonietta Rossi, Lidia Sautebin, Alessandro Carlucci, Paolo Abrescia, Carlo Pedone, Angela Ianaro and Giuseppe Cirino
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 716-722; DOI: https://doi.org/10.1124/jpet.111.189308
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