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(Circulation. 2003;108:2524.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Epiregulin as a Major Autocrine/Paracrine Factor Released From ERK- and p38MAPK-Activated Vascular Smooth Muscle Cells

Masanori Takahashi, MD^*; Ken’ichiro Hayashi, PhD^*; Kenji Yoshida, MD^*; Yasuyuki Ohkawa, PhD; Toshi Komurasaki, PhD; Akira Kitabatake, MD, PhD; Akira Ogawa, MD, PhD; Wataru Nishida, MD, PhD; Masahiko Yano, MD, PhD; Morito Monden, MD, PhD; Kenji Sobue, MD, PhD

From the Department of Neuroscience (K.H., Y.O., W.N., K.S.) and the Department of Surgery and Clinical Oncology (M.Y., M.M.), Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Cardiovascular Medicine, Hokkaido University, Graduate School of Medicine (M.T., A.K.), Sapporo, Japan; the Department of Neurosurgery, Iwate Medical University School of Medicine (K.Y., A.O.), Morioka, Japan; and the Molecular Biology Laboratory, Medical Research Laboratories, Taisho Pharmaceutical Co, Ltd (T.K.), Saitama, Japan.

Correspondence to Dr Kenji Sobue, Department of Neuroscience, Osaka University Graduate School of Medicine (D13), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail sobue{at}nbiochem.med.osaka-u.ac.jp

Received December 31, 2002; de novo received April 23, 2003; revision received July 18, 2003; accepted July 21, 2003.

Background— The coordinated activation of extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non–heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs).

Methods and Results— We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase–polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo.

Conclusions— Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.

Key Words: vasculature • remodeling • muscle, smooth • atherosclerosis

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