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

Abstract

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

Remnant Lipoproteins As Strong Key Particles to Atherogenesis

“…-VLDL induced SMC proliferation by activation of MAPK via G protein-coupled receptor-mediated transactivation of the epidermal growth factor (EGF) receptor 73) . Kawakami et al reported that RLP from hypertriglyceridemic patients induced SMC proliferation 74,75) .…”

Remnant Lipoproteins and Atherogenesis

“…However, the direct effects of RLPs on smooth muscle cell (SMC) have remained almost unknown. We reported for the first time that RLPs induced SMC proliferation, regardless of its oxidative stress (13), and more recently identified the molecular mechanisms by which RLPs induce proliferation of vascular SMCs (14). In the latter, we reported that RLPs from hypertriglyceridemic (HTG) patients stimulated SMC proliferation via epidermal growth factor (EGF) receptor transactivation and heparin-binding EGF-like growth factor (HB-EGF) shedding.…”

Remnant Lipoproteins are a Stronger Risk Factor for Cardiovascular Events than LDL-C - From the Studies of Autopsies in Sudden Cardiac Death Cases

“…A previous report has demonstrated that RLPs induce VSMC proliferation [82]; however, receptors for RLPs in VSMCs have not yet been well characterized until recently reported by Aramaki et al (83), although LRP in the liver, apoB-48-R in macrophages, and VLDL receptor in heart, skeletal muscle, adipose tissue, brain and macrophages [84,85] have been shown to act as a receptor for RLPs. LOX-1 expression is dynamically inducible by various proatherogenic stimuli, including tumor necrosis factor-(TNF-), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and Ox- These results suggested that RLP induced LOX-1 expression and enhance the activation of smooth muscle cells.…”