Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice

Circulation. 2000 Jul 4;102(1):75-81. doi: 10.1161/01.cir.102.1.75.

Abstract

Background: Oxidized LDL has been found within the subendothelial space, and it exhibits numerous atherogenic properties, including induction of inflammatory genes. We examined the possibility that variations in endothelial response to minimally modified LDL (MM-LDL) constitute one of the genetic components in atherosclerosis.

Methods and results: By a novel explant technique, endothelial cells (ECs) were isolated from the aorta of inbred mouse strains with different susceptibilities to diet-induced atherosclerosis. Responses to MM-LDL were evaluated by examining the expression of inflammatory genes involved in atherosclerosis, including monocyte chemotactic protein-1 (MCP-1) and macrophage-colony-stimulating factor (M-CSF), an oxidative stress gene, heme oxygenase-1 (HO-1), and other, noninflammatory, genes. ECs from the susceptible mouse strain C57BL/6J exhibited dramatic induction of MCP-1, M-CSF, and HO-1, whereas ECs from the resistant strain C3H/HeJ showed little or no induction. In contrast, ECs from the 2 strains responded similarly to lipopolysaccharide.

Conclusions: These data provide strong evidence that genetic factors in atherosclerosis act at the level of the vessel wall.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / cytology
  • Arteriosclerosis / genetics*
  • Arteriosclerosis / immunology
  • Arteriosclerosis / metabolism*
  • Blotting, Northern
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemotaxis / immunology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Genetic Predisposition to Disease
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Lipopolysaccharides / pharmacology
  • Lipoproteins, LDL / metabolism*
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism
  • Membrane Proteins
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Vasculitis / enzymology

Substances

  • CD36 Antigens
  • Chemokine CCL2
  • Lipopolysaccharides
  • Lipoproteins, LDL
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • oxidized low density lipoprotein
  • Macrophage Colony-Stimulating Factor
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse