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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:276.)
© 2004 American Heart Association, Inc.

Vascular Biology

High Glucose-Induced Upregulation of Osteopontin Is Mediated via Rho/Rho Kinase Pathway in Cultured Rat Aortic Smooth Muscle Cells

Harukiyo Kawamura; Koutaro Yokote; Sunao Asaumi; Kazuki Kobayashi; Masaki Fujimoto; Yoshiro Maezawa; Yasushi Saito; Seijiro Mori

From the Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Inohana, Chiba, Japan

Correspondence to Koutaro Yokote Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan. E-mail kyokote-cib{at}umin.ac.jp

Objective— Osteopontin is upregulated in the diabetic vascular wall and in vascular smooth muscle cells cultured under high glucose concentration. In the present study, we analyzed the mechanism of high glucose-induced upregulation of osteopontin in cultured rat aortic smooth muscle cells.

Methods and Results— We found that an inhibitor of Rho-associated protein kinase, Y-27632, suppressed osteopontin mRNA expression under high glucose concentration. Transfection of cells with a constitutive active Rho mutant, pSR-myc-RhoDA, enhanced osteopontin mRNA expression. Furthermore, incubation of cells under high glucose concentration activated Rho, indicating that Rho/Rho kinase pathway mediates high-glucose–stimulated osteopontin expression. Treatment of cells with an inhibitor of protein kinase C, GF109203X, and azaserine, an inhibitor of the hexosamine pathway, suppressed high glucose-induced Rho activation. Glucosamine treatment was shown to activate Rho. Treatment of cells with an inhibitor of MEK1, PD98059, suppressed osteopontin mRNA expression under high glucose concentration. Incubation of cells under high glucose concentration activated ERK. Finally, transfection of cells with pSR-myc-RhoDA also activated ERK.

Conclusions— In conclusion, our present findings support a notion that Rho/Rho kinase pathway functions downstream of protein kinase C and the hexosamine pathways and upstream of ERK in mediating high-glucose–induced upregulation of osteopontin expression.

Key Words: osteopontin • Rho • glucose • atherosclerosis • smooth muscle cells

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