title: Apolipoprotein A-I (ApoA-I) mimetic peptide P2a by restoring cholesterol esterification unmasks ApoA-I anti-inflammatory endogenous activity in vivo.
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 E(2) 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.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, via Domenico Montesano 49, 80131 Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.forename: Luisa
authors.initials: L
authors.lastname: Cigliano
authors.forename: Valentina
authors.initials: V
authors.lastname: Vellecco
authors.forename: Luca Domenico
authors.initials: LD
authors.lastname: D'Andrea
authors.forename: Barbara
authors.initials: B
authors.lastname: Ziaco
authors.forename: Antonietta
authors.initials: A
authors.lastname: Rossi
authors.forename: Lidia
authors.initials: L
authors.lastname: Sautebin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Carlucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Abrescia
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000097:blood / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000378:metabolism; D004951:Esterification; D006242:Haptoglobins / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; C571287:ApoA-I mimetic peptide P2a; D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D006242:Haptoglobins; D010455:Peptides; D051546:Cyclooxygenase 2; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D015232:Dinoprostone