Published Online
on November 17, 2003

A more recent version of this article appeared on November 25, 2003

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Submitted on July 30, 2002
Revised on July 15, 2003
Accepted on July 16, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: masa.vasc{at}tmd.ac.jp.

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

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