Masanori Yoshizumi1, Shoji Kagami2,, Yuki Suzaki1,
Koichiro Tsuchiya1, Hitoshi Houchi1, Tetsuhiro Hisayama3,
Hiroyuki Fukui3 and Toshiaki Tamaki1,*
Departments of 1Pharmacology and 2Pediatrics, The
University of Tokushima School of Medicine, Tokushima 770-8503, Japan
3Department of Pharmacology, Faculty of Pharmaceutical Sciences,
The University of Tokushima, Tokushima 770-8505, Japan
*Corresponding author.ﾊﾊFAX:+81-88-633-7062
E-mail: tamaki@basic.med.tokushima-u.ac.jp
Abstract: It was previously found that human chymase cleaves big
endothelins (ETs) at the Tyr31-Gly32 bond and produces
31-amino acid ETsﾊ(1-31). In the present study, human plasma concentrations
of ET-1ﾊ(1-31) and ET-1 were examined and the effect of synthetic ET-1ﾊ(1-31)
on the proliferation of cultured human mesangial cells (HMCs) was investigated.
The proliferative effect of ET-1ﾊ(1-31) was evaluated from the [3H]-thymidine
uptake. The activity of extracellular signal-regulated kinase (ERK) and
DNA binding activity of activator protein-1 were determined by using an
in-gel kinase assay and gel mobility shift assay, respectively. Immunoreactive
ET-1ﾊ(1-31) was detectable in plasma, but the level was slightly lower than
that of ET-1. ET-1ﾊ(1-31) increased [3H]-thymidine incorporation
in HMCs to a degree similar to that induced by ET-1. ET-1ﾊ(1-31) also activated
ERK1/2. Inhibition of protein kinaseﾊC and ERK kinase caused a reduction
of ET-1ﾊ(1-31)-induced ERK1/2 activation. The ERK1/2 activation was followed
by an increase in transcription factor activator protein-1 DNA binding activity.
These findings suggest that ET-1ﾊ(1-31) is a bioactive peptide in humans
and ET-1ﾊ(1-31) itself stimulates HMC proliferation.
Keywords: Endothelin-1ﾊ(1-31), Human chymase, Extracellular signal-regulated
kinase, Protein kinaseﾊC
Copyrightｩ The Japanese Pharmacological Society 2000
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