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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2095.)
© 2004 American Heart Association, Inc.

Vascular Biology

Altered PDGF-BB–Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells

Roles of Protein Kinase C-

Hiroshi Yamaguchi; Masahiko Igarashi; Akihiko Hirata; Naoko Sugae; Hiromi Tsuchiya; Yumi Jimbu; Makoto Tominaga; Takeo Kato

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.

Correspondence to Dr Masahiko Igarashi, Department of Laboratory Medicine, Yamagata University School of Medicine, 2-2-2, Iida-nishi, Yamagata 990-9585, Japan. E-mail migarasi{at}med.id.yamagata-u.ac.jp

Objective— We investigated the regulation of p38 mitogen-activated protein kinase (MAPK) 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 ß-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 MAPK 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)-ßII 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.

We investigated the regulation of p38 MAP kinase (MAPK) by platelet-derived growth factor (PDGF)-BB in diabetic rat vascular smooth muscle cells. PDGF-BB phosphorylated p38 via protein kinase C- and the subsequent MAPK kinase (MKK) 3/6, leading to cell growth regulation and the progression of a chronic inflammatory process in diabetes.

Key Words: p38 • PDGF-BB • VSMC • PKC • migration

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