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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:851.)
© 2004 American Heart Association, Inc.

Vascular Biology

Modulation of PPAR Expression and Inflammatory Interleukin-6 Production by Chronic Glucose Increases Monocyte/Endothelial Adhesion

Suseela Srinivasan; Melissa E. Hatley; Kelly B. Reilly; Eric C. Danziger; Catherine C. Hedrick

From the Division of Endocrinology and Metabolism, University of Virginia, Charlottesville.

Correspondence to Dr Catherine C. Hedrick, Division of Endocrinology & Metabolism, University of Virginia, PO Box 801394, 415 Lane Rd, MR5, Room G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu

Objective— We have previously reported increased monocyte adhesion to human aortic endothelial cells (HAECs) cultured in 25 mmol/L glucose (HG) compared with normal glucose (NG) (5.5 mmol/L). In this study, we explored mechanisms that contribute to increased monocyte adhesion by elevated glucose.

Methods and Results— We found that HAECs cultured in HG have increased production of the chemokine interleukin-6 (IL-6). We examined whether IL-6 directly modulated monocyte adhesion to EC. Inhibition of IL-6 using a neutralizing antibody significantly reduced glucose-mediated monocyte adhesion by 50%, and addition of IL-6 directly to human EC stimulated monocyte adhesion. PPAR has been reported to negatively regulate expression of IL-6 in vascular cells, so we examined PPAR-associated signaling in EC. A known PPAR agonist, Wy14,643, prevented glucose-mediated IL-6 production by EC and reduced glucose-mediated monocyte adhesion by 40%. HG-cultured HAEC had a 50% reduction in expression of PPAR compared with control EC. Primary aortic EC isolated from PPAR knockout (KO) mice showed increased monocyte adhesion compared with EC isolated from control mice. PPAR KO EC also had increased production of IL-6. Finally, we measured IL-6 levels in diabetic db/db mice and found significant 6-fold elevations in IL-6 levels in db/db EC.

Conclusions— These data indicate that IL-6 production is increased in diabetes and contributes to early vascular inflammatory changes. PPAR protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production.

Key Words: endothelium • monocytes • PPAR • atherosclerosis • interleukin-6

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