This Article Full Text Full Text (PDF) All Versions of this Article: 108/21/2679    most recent 01.CIR.0000093278.75565.87v1 Alert me when this article is cited 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 Kawakami, A. Articles by Yoshida, M. Search for Related Content PubMed PubMed Citation Articles by Kawakami, A. Articles by Yoshida, M. Related Collections Lipid and lipoprotein metabolism Cell signalling/signal transduction Smooth muscle proliferation and differentiation

(Circulation. 2003;108:2679.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Remnant Lipoprotein-Induced Smooth Muscle Cell Proliferation Involves Epidermal Growth Factor Receptor Transactivation

Akio Kawakami, MD; Akira Tanaka, MD; Tsuyoshi Chiba, PhD; Katsuyuki Nakajima, PhD; Kentaro Shimokado, MD; Masayuki Yoshida, MD

From the Departments of Medical Biochemistry (A.K., M.Y.) and Geriatrics and Vascular Medicine (A.K., T.C., K.S., M.Y.), Graduate School of Medicine, Tokyo Medical and Dental University; Department of Health and Nutrition (A.T.), College of Human Environmental Studies, Kanto-gakuin University; and Japan Immunoresearch Laboratories (K.N.), Takasaki, Japan.

Correspondence to Masayuki Yoshida, MD, Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Building D-256, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail masa.vasc{at}tmd.ac.jp

Received July 30, 2002; de novo received May 20, 2003; revision received July 15, 2003; accepted July 16, 2003.

Background— Remnant lipoproteins (RLPs) have been shown to play a causative role during atherosclerosis. Furthermore, it is known that vascular smooth muscle cell (SMC) proliferation is crucial for the development of atherosclerosis and restenosis after percutaneous coronary intervention. We examined the direct effect of RLPs on the proliferation and signal transduction of SMCs.

Methods and Results— Incubation in the presence of RLPs (20 mg cholesterol per dL) for 48 hours induced rat aortic SMC proliferation (2.3-fold over medium alone). RLPs also induced the phosphorylation of epidermal growth factor (EGF) receptor in SMCs, which was followed by the activation of mitogen-activated protein kinases. Moreover, the activation of protein kinase C (PKC) as well as the shedding of membrane-bound soluble heparin-binding EGF-like growth factor (HB-EGF) was observed after RLP treatment of SMCs, whereas PKC inhibitors and metalloprotease inhibitors inhibited RLP-induced EGF receptor transactivation and HB-EGF shedding in SMCs. Furthermore, anti-HB-EGF neutralizing antibody inhibited RLP-induced EGF receptor transactivation. Phosphorylation of EGF receptor and HB-EGF shedding were also observed in the aortas of apolipoprotein E–knockout mice but not in those of C57BL6 mice.

Conclusions— These results suggest that RLPs transactivate EGF receptor via PKC and HB-EGF shedding from SMCs, resulting in SMC proliferation.

Key Words: lipoproteins • muscle, smooth • signal transduction • atherosclerosis

This article has been cited by other articles:

				B. Bermudez, S. Lopez, Y. M. Pacheco, J. Villar, F. J.G. Muriana, J. D. Hoheisel, A. Bauer, and R. Abia Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery Cardiovasc Res, July 15, 2008; 79(2): 294 - 303. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Aikawa, N. Nitta, M. Yoshida, P. Libby, and F. M. Sacks Apolipoprotein CIII-Induced THP-1 Cell Adhesion to Endothelial Cells Involves Pertussis Toxin-Sensitive G Protein- and Protein Kinase C{alpha}-Mediated Nuclear Factor-{kappa}B Activation Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 219 - 225. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Aikawa, P. Alcaide, F. W. Luscinskas, P. Libby, and F. M. Sacks Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells Circulation, August 15, 2006; 114(7): 681 - 687. [Abstract] [Full Text] [PDF]

				A. Kawakami, M. Tani, T. Chiba, K. Yui, S. Shinozaki, K. Nakajima, A. Tanaka, K. Shimokado, and M. Yoshida Pitavastatin Inhibits Remnant Lipoprotein-Induced Macrophage Foam Cell Formation Through ApoB48 Receptor-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 424 - 429. [Abstract] [Full Text] [PDF]

				K. Oi, H. Shimokawa, J. Hiroki, T. Uwatoku, K. Abe, Y. Matsumoto, Y. Nakajima, K. Nakajima, S. Takeichi, and A. Takeshita Remnant Lipoproteins from Patients with Sudden Cardiac Death Enhance Coronary Vasospastic Activity Through Upregulation of Rho-Kinase Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 918 - 922. [Abstract] [Full Text]