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

Chu Huang Chen, Tao Jiang, Jun Hai Yang, Wei Jiang, Jonathan Lu, Gopal K. Marathe, Henry J. Pownall, Christie M. Ballantyne, Thomas M. McIntyre, Philip D. Henry, Chao Yuh Yang

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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 L5by 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.

Original languageEnglish (US)
Pages (from-to)2102-2108
Number of pages7
JournalCirculation
Volume107
Issue number16
DOIs
StatePublished - Apr 29 2003

Keywords

  • Apoptosis
  • Endothelium
  • Growth substances
  • Lipoproteins
  • Phospholipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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