on September 2, 2004
Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000144009.35400.65
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Submitted on March 3, 2004
Accepted on July 26, 2004
Altered PDGF-BB-Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells: Roles of Protein Kinase C-d
Hiroshi Yamaguchi ;
From Third Department of Internal Medicine (H.Y., N.S., H.T., Y.J., T.K.) and Department of Laboratory Medicine (M.I., A.H., M.T.), Yamagata University School of Medicine, Yamagata, Japan.
* To whom correspondence should be addressed. E-mail: migarasi{at}med.id.yamagata-u.ac.jp.
Objective--We investigated the regulation of p38 mitogen-activated protein kinase by platelet-derived growth factor (PDGF)-BB and its biological effects in cultured normal and diabetic rat vascular smooth muscle cells (VSMCs).
Methods and Results--VSMC growth from diabetic rats was faster than that from normal rats. The expression of the PDGF 
-receptor in diabetic VSMCs was significantly elevated compared with that in normal cells, and PDGF-BB-induced p38 phosphorylation in diabetic cells was more enhanced via MAP kinase kinase (MKK) 3/6. The level of PKC activity in diabetic cells increased more than that in normal cells with or without PDGF-BB. Although protein kinase C (PKC)-II and PKC-
were activated by diabetes, PDGF-BB could further enhance the level of PKC- alone. PDGF-BB-induced cell migration was more elevated in diabetic VSMCs, and the increase was significantly inhibited by SB-203580, rottlerin, and antisense oligodeoxynucleotides for PKC-. PDGF-BB-induced p38 phosphorylation also regulated cell growth, cyclooxygenase-2 levels, and arachidonic acid release, but not apoptosis. These levels were more elevated in diabetic cells, which were inhibited by SB-203580.
Conclusions--Our study established that PDGF-BB phosphorylated p38 via PKC- and the subsequent MKK 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetic VSMCs.
Key words: p38 • PDGF-BB • VSMC • PKC • migration
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