Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells.
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).


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.
Takahashi
Masanori
M
Department of Neuroscience, Osaka University Graduate School of Medicine (D13), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hayashi
Ken'ichiro
K
Yoshida
Kenji
K
Ohkawa
Yasuyuki
Y
Komurasaki
Toshi
T
Kitabatake
Akira
A
Ogawa
Akira
A
Nishida
Wataru
W
Yano
Masahiko
M
Monden
Morito
M
Sobue
Kenji
K
D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D019898:Autocrine Communication / Q000502:physiology*; D000077214:Becaplermin; D015415:Biomarkers / Q000032:analysis; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066260:Epiregulin; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
D015415:Biomarkers; D017077:Culture Media, Conditioned; C587880:EREG protein, human; D066260:Epiregulin; C587882:Ereg protein, rat; D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases