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Distinct apolipoprotein E isoform preference for inhibition of smooth muscle cell migration and proliferation
Michelle Zeleny1, Debi K Swertfeger, Karl H Weisgraber
1Center for Lipid and Arteriosclerosis Studies, Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Abstract:
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.
Insights
Apolipoprotein E3 (apoE3) effectively inhibits smooth muscle cell proliferation stimulated by platelet-derived growth factor (PDGF), while apoE2 and apoE4 show less efficacy. All apoE isoforms equally inhibit PDGF-directed cell migration.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Molecular Biology
Background:
- Apolipoprotein E (apoE) plays a role in lipid metabolism and cardiovascular health.
- Different isoforms of apoE (apoE2, apoE3, apoE4) are associated with varying risks of coronary artery disease.
- Platelet-derived growth factor (PDGF) is a key regulator of smooth muscle cell proliferation and migration.
Purpose of the Study:
- To compare the effectiveness of human apolipoprotein E (apoE) isoforms in inhibiting PDGF-stimulated smooth muscle cell proliferation and migration.
- To elucidate the mechanisms underlying apoE's differential effects on cell proliferation versus migration.
Main Methods:
- Primary mouse aortic smooth muscle cells were incubated with varying concentrations of human apoE2, apoE3, and apoE4.
- Cells were stimulated with platelet-derived growth factor (PDGF).
- Smooth muscle cell proliferation and migration were quantified.
Main Results:
- Apolipoprotein E3 (apoE3) demonstrated dose-dependent inhibition of PDGF-stimulated smooth muscle cell proliferation, with >50% inhibition at 15 microg/mL.
- ApoE2 was less effective than apoE3, and apoE4 showed no significant inhibition of proliferation.
- All apoE isoforms (apoE2, apoE3, apoE4) were equally effective in inhibiting PDGF-directed smooth muscle cell migration.
Conclusions:
- The differential efficacy of apoE isoforms in inhibiting smooth muscle cell proliferation suggests isoform-specific mechanisms.
- Inhibition of proliferation by apoE likely involves binding to heparan sulfate proteoglycans.
- Inhibition of migration by apoE likely involves binding to the low-density lipoprotein receptor related protein.
- The low efficacy of apoE4 in inhibiting proliferation may contribute to its association with increased coronary artery disease risk.