This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ishigami, M. Articles by Hui, D. Y. Search for Related Content PubMed PubMed Citation Articles by Ishigami, M. Articles by Hui, D. Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Smooth muscle proliferation and differentiation

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1020.)
© 2000 American Heart Association, Inc.

Vascular Biology

Apolipoprotein E Inhibition of Vascular Smooth Muscle Cell Proliferation but Not the Inhibition of Migration Is Mediated Through Activation of Inducible Nitric Oxide Synthase

Masato Ishigami; Debi K. Swertfeger; Michele S. Hui; Norman A. Granholm; David Y. Hui

From the Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to David Y. Hui, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Bethesda Ave, Cincinnati, OH 45267-0529.

Abstract—Initial experiments revealed that low concentrations of apolipoprotein (apo) E (0.1 to 5 µg/mL) were effective in inhibiting platelet-derived growth factor (PDGF)–directed smooth muscle cell (SMC) migration by 60% to 80%. In contrast, higher concentrations of apoE, at 25 and 50 µg/mL, were necessary to achieve similar inhibition of PDGF-induced SMC proliferation. The potential role of nitric oxide (NO) in mediating the inhibitory effects of apoE was explored. Results showed that, although 0.1 to 5 µg/mL of apoE had no effect on NO production by SMCs, physiological concentrations of apoE (25 to 50 µg/mL) enhanced NO synthesis by 2-fold in a dose-dependent manner (P<0.001). Reverse transcription–polymerase chain reaction amplification of RNA obtained from control and apoE-treated SMCs demonstrated a direct role of apoE in activating inducible nitric oxide synthase (iNOS) gene expression. The apoE-induced nitric oxide production was significantly reduced by coincubation of the cells with aminoguanidine or N^G-monomethyl-L-arginine (P<0.05) or with antisense iNOS oligodeoxynucleotides (P<0.01). Moreover, the inhibition of iNOS was shown to overcome apoE suppression of PDGF-induced vascular SMC proliferation. However, apoE suppression of PDGF-directed SMC migration was not affected by these treatments. Taken together, these results document that apoE exerts its inhibitory effects on cell proliferation via activation of iNOS. However, apoE inhibition of cell migration is mediated by a mechanism independent of iNOS activation.

Key Words: apolipoprotein E • smooth muscle cell proliferation • nitric oxide • smooth muscle cell migration

This article has been cited by other articles:

				A. Kawamura, D. Baitsch, R. Telgmann, R. Feuerborn, G. Weissen-Plenz, C. Hagedorn, K. Saku, S.-M. Brand-Herrmann, A. von Eckardstein, G. Assmann, et al. Apolipoprotein E Interrupts Interleukin-1{beta} Signaling in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1610 - 1617. [Abstract] [Full Text] [PDF]

				M. Altenburg, L. Johnson, J. Wilder, and N. Maeda Apolipoprotein E4 in Macrophages Enhances Atherogenesis in a Low Density Lipoprotein Receptor-dependent Manner J. Biol. Chem., March 16, 2007; 282(11): 7817 - 7824. [Abstract] [Full Text] [PDF]

				A. E. Mullick, A. F. Powers, R. S. Kota, S. D. Tetali, J. P. Eiserich, and J. C. Rutledge Apolipoprotein E3- and Nitric Oxide-Dependent Modulation of Endothelial Cell Inflammatory Responses Arterioscler Thromb Vasc Biol, February 1, 2007; 27(2): 339 - 345. [Abstract] [Full Text] [PDF]

				Z. W. Q. Moore and D. Y. Hui Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase J. Lipid Res., October 1, 2005; 46(10): 2083 - 2090. [Abstract] [Full Text] [PDF]

				Y.-C. Chen, G. Pohl, T.-L. Wang, P. J. Morin, B. Risberg, G. B. Kristensen, A. Yu, B. Davidson, and I.-M. Shih Apolipoprotein E Is Required for Cell Proliferation and Survival in Ovarian Cancer Cancer Res., January 1, 2005; 65(1): 331 - 337. [Abstract] [Full Text] [PDF]

				T. Aoki, D. Sato, Y. Li, T. Takino, H. Miyamori, and H. Sato Cleavage of Apolipoprotein E by Membrane-Type Matrix Metalloproteinase-1 Abrogates Suppression of Cell Proliferation J. Biochem., January 1, 2005; 137(1): 95 - 99. [Abstract] [Full Text] [PDF]

				Z. W.Q. Moore, B. Zhu, D. G. Kuhel, and D. Y. Hui Vascular Apolipoprotein E Expression and Recruitment from Circulation to Modulate Smooth Muscle Cell Response to Endothelial Denudation Am. J. Pathol., June 1, 2004; 164(6): 2109 - 2116. [Abstract] [Full Text] [PDF]

				Y. Zhu and D. Y. Hui Apolipoprotein E Binding to Low Density Lipoprotein Receptor-related Protein-1 Inhibits Cell Migration via Activation of cAMP-dependent Protein Kinase A J. Biol. Chem., September 19, 2003; 278(38): 36257 - 36263. [Abstract] [Full Text] [PDF]

				L. Krimbou, M. Marcil, H. Chiba, and J. Genest Jr. Structural and functional properties of human plasma high density-sized lipoprotein containing only apoE particles J. Lipid Res., May 1, 2003; 44(5): 884 - 892. [Abstract] [Full Text] [PDF]

				D. Eguchi, L. V. d'Uscio, C. Wambi, D. Weiler, I. Kovesdi, T. O'Brien, and Z. S. Katusic Inhibitory effect of recombinant iNOS gene expression on vasomotor function of canine basilar artery Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2560 - H2566. [Abstract] [Full Text] [PDF]

				B. Zhu, C. A. Reardon, G. S. Getz, and D. Y. Hui Both Apolipoprotein E and Immune Deficiency Exacerbate Neointimal Hyperplasia After Vascular Injury in Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 450 - 455. [Abstract] [Full Text] [PDF]

				G. S. Getz Mouse Model of Unstable Atherosclerotic Plaque? Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2503 - 2505. [Full Text] [PDF]

				L. K. Curtiss ApoE in Atherosclerosis : A Protein With Multiple Hats Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1852 - 1853. [Full Text] [PDF]

				D. K. Swertfeger and D. Y. Hui Apolipoprotein E Receptor Binding Versus Heparan Sulfate Proteoglycan Binding in Its Regulation of Smooth Muscle Cell Migration and Proliferation J. Biol. Chem., June 29, 2001; 276(27): 25043 - 25048. [Abstract] [Full Text] [PDF]

				D. K. Swertfeger, G. Bu, and D. Y. Hui Low Density Lipoprotein Receptor-related Protein Mediates Apolipoprotein E Inhibition of Smooth Muscle Cell Migration J. Biol. Chem., February 1, 2002; 277(6): 4141 - 4146. [Abstract] [Full Text] [PDF]