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(Circulation Research. 2004;94:1515.)
© 2004 American Heart Association, Inc.

Molecular Medicine

PPAR Agonists Ameliorate Endothelial Cell Activation via Inhibition of Diacylglycerol–Protein Kinase C Signaling Pathway

Role of Diacylglycerol Kinase

Emily Verrier^*, Lijun Wang^*, Carol Wadham, Nathaniel Albanese, Chris Hahn, Jennifer R. Gamble, V. Krishna K. Chatterjee, Mathew A. Vadas, Pu Xia

From Signal Transduction Laboratory (E.V., L.W., C.W., N.A., M.A.V., P.X.), Hanson Institute, Institute of Medical and Veterinary Science (C.H., J.R.G.), and Department of Medicine, University of Adelaide (J.R.G., M.A.V., P.X.), Australia; and Department of Medicine (V.K.K.C.), University of Cambridge, UK.

Correspondence to Pu Xia, MD, Signal Transduction Laboratory, Hanson Institute, Frome Road, PO Box 14 Rundle Mall, Adelaide, SA 5000, Australia. E-mail pu.xia{at}imvs.sa.gov.au

Subject— Peroxisome proliferator-activated receptor (PPAR)- agonists are emerging as potential protectors against inflammatory cardiovascular diseases including atherosclerosis and diabetic complications. However, their molecular mechanism of action within vasculature remains unclear. We report here that PPAR agonists, thiazolidinedione class drugs (TZDs), or 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ2) were capable of activating diacylglycerol (DAG) kinase (DGK), resulting in attenuation of DAG levels and inhibition of protein kinase C (PKC) activation. The PPAR agonist-induced DGK was completely blocked by a dominant-negative mutant of PPAR, indicating an essential receptor-dependent action. Importantly, the suppression of DAG-PKC signaling pathway was functional linkage to the anti-inflammatory properties of PPAR agonists in endothelial cells (EC), characterized by the inhibition of proinflammatory adhesion molecule expression and adherence of monocytes to the activated EC induced by high glucose. These findings thus demonstrate a novel molecular action of PPAR agonists to suppress the DAG-PKC signaling pathway via upregulation of an endogenous attenuator, DGK.

Key Words: PPAR • diacylglycerol kinase • protein kinase C • vascular inflammation • diabetic complications

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