PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase.
Subject- Peroxisome proliferator-activated receptor (PPAR)-gamma 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 PPARgamma agonists, thiazolidinedione class drugs (TZDs), or 15-deoxy-Delta12,14-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 PPARgamma agonist-induced DGK was completely blocked by a dominant-negative mutant of PPARgamma, indicating an essential receptor-dependent action. Importantly, the suppression of DAG-PKC signaling pathway was functional linkage to the anti-inflammatory properties of PPARgamma 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 PPARgamma agonists to suppress the DAG-PKC signaling pathway via upregulation of an endogenous attenuator, DGK.
Verrier
Emily
E
Signal Transduction Laboratory, Hanson Institute, Adelaide, SA, Australia.
Wang
Lijun
L
Wadham
Carol
C
Albanese
Nathaniel
N
Hahn
Chris
C
Gamble
Jennifer R
JR
Chatterjee
V Krishna K
VK
Vadas
Mathew A
MA
Xia
Pu
P
D000818:Animals; D001011:Aorta; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000517:prevention & control; D019852:Diacylglycerol Kinase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004075:Diglycerides / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects; D014471:Umbilical Veins; D014657:Vasculitis / Q000517:prevention & control
C477819:15-deoxyprostaglandin J2; D015815:Cell Adhesion Molecules; D002839:Chromans; D004075:Diglycerides; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000077288:Troglitazone; D005947:Glucose; D015230:Prostaglandin D2; C039671:ciglitazone