Remnant lipoprotein-induced smooth muscle cell proliferation involves epidermal growth factor receptor transactivation.
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.


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.
Kawakami
Akio
A
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.
Tanaka
Akira
A
Chiba
Tsuyoshi
T
Nakajima
Katsuyuki
K
Shimokado
Kentaro
K
Yoshida
Masayuki
M
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000302:isolation & purification / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D005799:Genes, Dominant; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins / Q000302:isolation & purification / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000302:isolation & purification / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D014280:Triglycerides / Q000302:isolation & purification / Q000494:pharmacology
D001057:Apolipoproteins E; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D043562:Receptors, G-Protein-Coupled; D014280:Triglycerides; C112017:remnant-like particle cholesterol; D004815:Epidermal Growth Factor; D002784:Cholesterol; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine