Abstract
This study showed that synthetic peptides containing either a single copy or tandem repeat of the receptor binding domain sequence of apolipoprotein (apo) E, or a peptide containing its C-terminal heparin binding domain, apoE-(211-243), were all effective inhibitors of platelet-derived growth factor (PDGF)-stimulated smooth muscle cell proliferation. In contrast, only the peptide containing a tandem repeating unit of the receptor binding domain sequence of apoE, apoE-(141-155)(2), was capable of inhibiting PDGF-directed smooth muscle cell migration. Peptide containing only a single unit of this sequence, apoE-(141-155), or the apoE-(211-243) peptide were ineffective in inhibiting PDGF-directed smooth muscle cell migration. Additional experiments showed that reductively methylated apoE, which is incapable of receptor binding yet retains its heparin binding capability, was equally effective as apoE in inhibiting PDGF-stimulated smooth muscle cell proliferation. However, reductively methylated apoE was unable to inhibit smooth muscle cell migration toward PDGF. Additionally, the receptor binding domain-specific apoE antibody 1D7 also mitigated the anti-migratory properties of apoE on smooth muscle cells. Finally, pretreatment of cells with heparinase failed to abolish apoE inhibition of smooth muscle cell migration. Taken together, these data documented that apoE inhibition of PDGF-stimulated smooth muscle cell proliferation is mediated by its binding to heparan sulfate proteoglycans, while its inhibition of cell migration is mediated through apoE binding to cell surface receptors.
Highlights
Research in the past two decades has clearly demonstrated that apolipoprotein1 E protects against vascular disease [1]
Pretreatment of cells with heparinase failed to abolish apoE inhibition of smooth muscle cell migration. These data documented that apoE inhibition of platelet-derived growth factor (PDGF)-stimulated smooth muscle cell proliferation is mediated by its binding to heparan sulfate proteoglycans, while its inhibition of cell migration is mediated through apoE binding to cell surface receptors
Results of the current study showed that peptides containing at least one copy of either the receptor binding domain or the distal heparin binding site of apoE were capable of inhibiting PDGF-stimulated smooth muscle cell proliferation
Summary
Research in the past two decades has clearly demonstrated that apolipoprotein (apo) E protects against vascular disease [1]. Atherosclerotic lesions in mice with only one copy of the apoE gene (apoEϩ/Ϫ) were 10 times more severe than lesions in wild type mice that were fed a high fat/high cholesterol diet, despite relative similar cholesterol levels between the two groups of animals (326 versus 238 mg/dl). We have shown that apoE inhibits platelet-derived growth factor (PDGF)- or oxidized LDL-induced smooth muscle cell migration and proliferation [8]. ApoE inhibition of smooth muscle cell proliferation was shown to be due to cell cycle arrest resulting from the inhibition of growth factor-induced cyclin D1 activation [8] The mechanism of this inhibition appeared to be mediated through inducible nitricoxide synthase signaling pathways [9].
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