Distinct apolipoprotein E isoform preference for inhibition of smooth muscle cell migration and proliferation.
The current study compared the effectiveness of the various human apolipoprotein E (apoE) isoforms in inhibiting platelet-derived growth factor- (PDGF-) stimulated smooth muscle cell proliferation and migration. The incubation of primary mouse aortic smooth muscle cells with apoE3 resulted in dose-dependent inhibition of smooth muscle cells stimulated by 10 ng/mL PDGF. Greater than 50% inhibition of smooth muscle cell proliferation was observed at 15 microg/mL of human apoE3. Human apoE2 was less effective, requiring a higher concentration to achieve inhibition comparable to that of apoE3. Human apoE4 was the least effective of the apoE isoforms with no significant inhibition of cell proliferation observed at concentrations up to 15 microg/mL. Interestingly, apoE inhibition of PDGF-directed smooth muscle cell migration did not show preference for any apoE isoforms. Human apoE2, apoE3, and apoE4 were equally effective in inhibiting smooth muscle cell migration toward PDGF. These results are consistent with previous data showing that apoE inhibition of smooth muscle cell proliferation is mediated through its binding to heparan sulfate proteoglycans, whereas its inhibition of cell migration is mediated via binding to the low-density lipoprotein receptor related protein. The low efficiency of apoE4 to inhibit smooth muscle cell proliferation also suggested another mechanism to explain the association between the apolipoprotein epsilon4 allele with increased risk of coronary artery disease.
Zeleny
Michelle
M
Center for Lipid and Arteriosclerosis Studies, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Swertfeger
Debi K
DK
Weisgraber
Karl H
KH
Hui
David Y
DY
D000818:Animals; D001011:Aorta; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D006131:Growth Inhibitors; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins