eNOS activation by HDL is impaired in genetic CETP deficiency

Maurizio Averna, Angelo Baldassare Cefalu', Fabrizio Veglia, Guido Franceschini, Alice Ossoli, Silvia Pozzi, G. Kees Hovingh, Jan Albert Kuivenhoven, Laura Calabresi, Peter Nilsson, Monica Gomaraschi

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27 Citations (Scopus)

Abstract

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.
Original languageEnglish
Number of pages0
JournalPLoS One
Volume9
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Averna, M., Cefalu', A. B., Veglia, F., Franceschini, G., Ossoli, A., Pozzi, S., Hovingh, G. K., Kuivenhoven, J. A., Calabresi, L., Nilsson, P., & Gomaraschi, M. (2014). eNOS activation by HDL is impaired in genetic CETP deficiency. PLoS One, 9.