Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Academic Article uri icon

Overview

abstract

  • BACKGROUND: Apoptosis of vascular endothelial cells (ECs) can be induced in vitro by experimentally modified LDL. Description of proapoptotic circulating lipoproteins may significantly enhance understanding of atherothrombosis pathophysiology. METHODS AND RESULTS: Fast protein liquid chromatography of LDL samples from 7 asymptomatic, hypercholesterolemic patients yielded subfractions L1-L5 in increasing electronegativity. L4 and L5 were not detectable or collectible in normolipidemic samples. In bovine aortic EC cultures, L5 induced marked apoptosis and L4 had a mild effect, whereas hypercholesterolemic or normolipidemic L1-L3 had negligible effects. Compared with copper-oxidized LDL, L5 was only mildly oxidized, although its propensity to form conjugated dienes in response to copper exceeded that of other subfractions. L5-induced apoptosis was associated with suppressed fibroblast growth factor 2 (FGF-2) transcription, as assessed by nuclear run-on analysis. Degrading platelet-activating factor (PAF)-like lipids in L5 by a recombinant PAF acetylhydrolase prevented both FGF-2 downregulation and apoptosis. Furthermore, the ability of L5 lipid extract to induce calcium influx into neutrophils was lost after pretreatment of the extract with PAF acetylhydrolase. FGF-2 supplementation, PAF receptor (PAFR) blockade with WEB-2086, and inactivation of PAFR-coupled Gi protein with pertussis toxin all effectively attenuated L5-induced apoptosis. CONCLUSIONS: Our findings indicate that a highly electronegative, mildly oxidized LDL subfraction present in human hypercholesterolemic but not normolipidemic plasma can induce apoptosis in cultured ECs. The evidence that a freshly isolated LDL species modulates transcription of FGF-2 may provide a physiological insight into the mechanism of vascular EC apoptosis in hypercholesterolemia.

publication date

  • April 14, 2003

Research

keywords

  • Apoptosis
  • Endothelium, Vascular
  • Fibroblast Growth Factor 2
  • Hypercholesterolemia
  • Lipoproteins, LDL

Identity

Scopus Document Identifier

  • 0038416942

PubMed ID

  • 12695302

Additional Document Info

volume

  • 107

issue

  • 16