title: Structure-function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells.
abstract: Apolipoprotein (apoE) E is a multifunctional protein that plays a critical role in atherogenesis, in part by regulating the intimal proliferation of vascular smooth muscle cells. Recently, a novel cyclooxygenase (COX)-2 pathway was shown to contribute to the anti-proliferative action of human apoE3 in vascular smooth muscle cells (VSMC). Here, we provide insight into the structure-function properties by which apoE mediates these effects. ApoE3 is most effective in promoting COX-2 expression as a lipid-free protein and is less active after lipidation. Alterations in the stability of the helix bundle N-terminal domain of apoE that contains the binding site for the low density lipoprotein (LDL) receptor and heparin do not affect the up-regulation of the COX-2 pathway. In addition, the apoE2, 3, and 4 isoforms are all capable of up-regulating the COX-2 pathway. Finally, the effect of apoE on COX-2 was found to be independent of expression on the VSMC surface of the LDL receptor and heparan sulfate proteoglycans (HSPG). In summary, our data indicates that apoE, particularly in the lipid-free state, can up-regulate COX-2 in murine vascular smooth muscle cells apparently independently of binding to the LDLR, LRP or HSPG.
authors.affiliation: Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
authors.forename: Kamilah
authors.initials: K
authors.lastname: Ali
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
authors.forename: Sissel
authors.initials: S
authors.lastname: Lund-Katz
authors.affiliation: Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
authors.forename: John
authors.initials: J
authors.lastname: Lawson
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
authors.affiliation: Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States. Electronic address: rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000737:chemistry / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D053318:Apolipoprotein E3; D019812:Heparan Sulfate Proteoglycans; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2