eNOS activation by HDL is impaired in genetic CETP deficiency.
Mutations in the CETP gene resulting in defective CETP activity have been shown to cause remarkable elevations of plasma HDL-C levels, with the accumulation in plasma of large, buoyant HDL particles enriched in apolipoprotein E. Genetic CETP deficiency thus represents a unique tool to evaluate how structural alterations of HDL impact on HDL atheroprotective functions. Aim of the present study was to assess the ability of HDL obtained from CETP-deficient subjects to protect endothelial cells from the development of endothelial dysfunction. HDL isolated from one homozygous and seven heterozygous carriers of CETP null mutations were evaluated for their ability to down-regulate cytokine-induced cell adhesion molecule expression and to promote NO production in cultured endothelial cells. When compared at the same protein concentration, HDL and HDL3 from carriers proved to be as effective as control HDL and HDL3 in down-regulating cytokine-induced VCAM-1, while carrier HDL2 were more effective than control HDL2 in inhibiting VCAM-1 expression. On the other hand, HDL and HDL fractions from carriers of CETP deficiency were significantly less effective than control HDL and HDL fractions in stimulating NO production, due to a reduced eNOS activating capacity, likely because of a reduced S1P content. In conclusion, the present findings support the notion that genetic CETP deficiency, by affecting HDL particle structure, impacts on HDL vasculoprotective functions. Understanding of these effects might be important for predicting the outcomes of pharmacological CETP inhibition.
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Monica
M
Gomaraschi
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Alice
A
Ossoli
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Silvia
S
Pozzi
Department of Clinical Sciences, University Hospital, Malmö, Sweden.
Peter
P
Nilsson
Department of Internal Medicine and Medical Specialties, Policlinico "Paolo Giaccone", University of Palermo, Palermo, Italy.
Angelo B
AB
Cefalù
Department of Internal Medicine and Medical Specialties, Policlinico "Paolo Giaccone", University of Palermo, Palermo, Italy.
Maurizio
M
Averna
University Medical Center Groningen, Groningen, The Netherlands.
Jan Albert
JA
Kuivenhoven
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
G Kees
GK
Hovingh
Istituto Cardiologico Monzino, Milano, Italy.
Fabrizio
F
Veglia
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Guido
G
Franceschini
Center E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Laura
L
Calabresi
D053480:Cholesterol Ester Transfer Proteins / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology; D006720:Homozygote; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics*; D008074:Lipoproteins / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry*; D009154:Mutation; D009569:Nitric Oxide / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D053480:Cholesterol Ester Transfer Proteins; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III