title: Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency.
abstract: The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend= 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold,P= 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%;PTrend= 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality.
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gomaraschi
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Ossoli
authors.affiliation: Centro Dislipidemie, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.
authors.forename: Samuela
authors.initials: S
authors.lastname: Castelnuovo
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Simonelli
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pavanello
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Balzarotti
authors.affiliation: Atherosclerosis Center, Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.affiliation: Atherosclerosis Center, Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Costanzo
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sampietro
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vaudo
authors.affiliation: Monzino Cardiologic Institute, IRCCS, Milano, Italy.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: Monzino Cardiologic Institute, IRCCS, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.affiliation: Section of Chemical and Biomolecular Sciences, DeFENS, Università degli Studi di Milano, Milano, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Franceschini
authors.affiliation: Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari Università degli Studi di Milano, Milano, Italy laura.calabresi@unimi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Calabresi
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000172:deficiency* / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000172:deficiency* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000378:metabolism* / Q000473:pathology*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008075:Lipoproteins, HDL; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
keywords: apolipoprotein A-II; endothelium; high density lipoprotein; lecithin:cholesterol acyltransferase; nitric oxide