Phospholipase D Isozymes Mediate Epigallocatechin Gallate-induced Cyclooxygenase-2 Expression in Astrocyte Cells

Kim, Shi Yeon; Ahn, Bong Hyun; Min, Kyoung Jin; Lee, Young Han; Joe, Eun Hye; Min, Do Sik

doi:10.1074/jbc.m402085200

Cited by 39 publications

(35 citation statements)

References 54 publications

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“…We sought to determine the dependence of PAR1 and PAR4 on LPP-1-mediated DAG production. Platelets were pretreated with either propranolol, a ␤-AR antagonist known to inhibit LPP-1 (Kanaho et al, 1991;Fukami and Takenawa, 1992;Kim et al, 2004), or nadolol, a chemically similar ␤-AR antagonist without effects on LPP-1 signaling. We first measured the dose-dependent effects of propranolol and nadolol on aggregation stimulated by thrombin, PAR1-AP, and PAR4-AP (Fig.…”

Section: Resultsmentioning

confidence: 99%

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Holinstat¹,

Voss²,

Bilodeau³

et al. 2006

Mol Pharmacol

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Pathological conditions such as coronary artery disease are clinically controlled via therapeutic regulation of platelet activity. Thrombin, through protease-activated receptor (PAR) 1 and PAR4, plays a central role in regulation of human platelet function in that it is known to be the most potent activator of human platelets. Currently, direct thrombin inhibitors used to block platelet activation result in unwanted side effects of excessive bleeding. An alternative therapeutic strategy would be to inhibit PAR-mediated intracellular platelet signaling pathways. To elucidate the best target, we are studying differences between the two platelet thrombin receptors, PAR1 and PAR4, in mediating thrombin's action. In this study, we show that platelet activation by PAR1-activating peptide (PAR1-AP) requires a phospholipase D (PLD)-mediated phosphatidic acid (PA) signaling pathway. We show that this PAR1-specific PA-mediated effect is not regulated through differential granule secretion after PARinduced platelet activation. Perturbation of this signaling pathway via inhibition of lipid phosphate phosphatase-1 (LPP-1) by propranolol or inhibition of the phosphatidylcholine-derived phosphatidic acid (PA) formation by PLD with a primary alcohol significantly attenuated platelet activation by PAR1-AP. Platelet activation by thrombin or PAR4-AP was insensitive to these inhibitors. Furthermore, these inhibitors significantly attenuated activation of Rap1 after stimulation by PAR1-AP but not thrombin or PAR4-AP. Because PA metabolites such as diacylglycerol play an important role in intracellular signaling, identifying crucial differences in PA regulation of PAR-induced platelet activation may lead to a greater understanding of the role of PAR1 versus PAR4 in progression of thrombosis.Platelets are regulated through numerous agonist-induced signaling pathways, the most potent of which is thrombin (Davey and Luscher, 1967;Jamieson, 1997). Human platelets express two functional thrombin receptors, protease activated receptor-1 and -4 (PAR1 and PAR4) (Kahn et al., 1998;Coughlin, 2005), whereas mouse platelets express PAR3 and PAR4. Previous work from our lab has indicated that PAR1 and PAR4 mediate platelet activation through distinct signaling pathways (Holinstat et al., 2006). How differential signaling through the thrombin receptors is regulated and the potential physiological consequences of selective activation of PAR1 and PAR4 remain unclear. Several intermediates within this signaling scheme, such as PKC␣ and the small GTPase Rap1 have been identified to be important to regulating platelet function (Franke et al., 2000;Chrzanowska-Wodnicka et al., 2005). Genetic studies in the mouse have confirmed the role of Rap1b in platelet aggregation and subsequent clot formation (Chrzanowska-Wodnicka et al., 2005). How Rap1 is involved in the initial and irreversible phases of platelet aggregation (Franke et al., 2000) and whether Rap1 is differentially regulated in human platelets by PAR1 and PAR4 remain elusive.In mouse pla...

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Section: Resultsmentioning

confidence: 99%

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Holinstat¹,

Voss²,

Bilodeau³

et al. 2006

Mol Pharmacol

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“…PLD activity was quantified as described (21). Briefly, the cells were labeled with [ 3 H]myristic acid for 12 h and incubated first with EGCG (as indicated) and then with 0.3% 1-butanol for 50 min.…”

Section: Other Methodsmentioning

confidence: 99%

“…In our search for such tools, we came across epigallocatechin gallate (EGCG), a monomeric phenol of the catechin group that is found in green tea (20). It has been shown to activate PLD (21) and thus has the potential to stimulate the assembly of cytosolic lipid droplets (9; L. Furthermore, EGCG has been shown to influence the secretion of apoB-100 in HepG2 cells (22).…”

mentioning

confidence: 99%

Epigallocatechin gallate increases the formation of cytosolic lipid droplets and decreases the secretion of apoB-100 VLDL

Li¹,

Stillemark-Billton²,

Beck³

et al. 2006

Journal of Lipid Research

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Epigallocatechin gallate (EGCG) increases the formation of cytosolic lipid droplets by a mechanism that is independent of the rate of triglyceride biosynthesis and involves an enhanced fusion between lipid droplets, a process that is crucial for their growth in size. EGCG treatment reduced the secretion of both triglycerides and apolipoprotein B-100 (apoB-100) VLDLs but not of transferrin, albumin, or total proteins, indicating that EGCG diverts triglycerides from VLDL assembly to storage in the cytosol. This is further supported by the observed increase in both intracellular degradation of apoB-100 and ubiquitination of the protein (indicative of increased proteasomal degradation) in EGCG-treated cells. EGCG did not interfere with the microsomal triglyceride transfer protein, and the effect of EGCG on the secretion of VLDLs was found to be independent of the LDL receptor.Thus, our results indicate that EGCG promotes the accumulation of triglycerides in cytosolic lipid droplets, thereby diverting lipids from the assembly of VLDL to storage in the cytosol. Our results also indicate that the accumulation of lipids in the cytosol is not always associated with increased secretion of VLDL.-Li, L., P. Stillemark-Billton, C. Accumulation of triglycerides, particularly in the liver and skeletal muscle, is associated with metabolic disorders such as insulin resistance and type 2 diabetes (1, 2), diseases that are strong risk factors for cardiovascular diseases. Accumulation of triglycerides in the liver is also the landmark of nonalcoholic fatty liver disease, which results in inflammation and liver damage (3). Moreover, the stores of triglyceride in the liver fuel the assembly and secretion of VLDLs (3-6). Thus, it is obvious that elucidation of the mechanism of the storage of lipid in the cytosol is important for our understanding of the pathogenesis of major metabolic diseases.Triglycerides are stored in the cytosol in the form of lipid droplets (also referred to as lipid bodies) (for reviews, see 7, 8). These droplets are formed from microsomes (9; see also 7, 8 for reviews) as a primordial droplet with a diameter of z0.1 Am It has been demonstrated that the fatty acids used for the biosynthesis of VLDL triglycerides are derived from triglycerides stored in the liver (3). The triglycerides are hydrolyzed and reesterified into new triglycerides before being assembled into VLDL (4-6). VLDLs are assembled in a complex series of events (for reviews, see 11-16), starting with the formation of a primordial particle (pre-VLDL) during the translation and translocation of apolipoprotein B-100 (apoB-100) to the lumen of the endoplasmic reticulum. This step is catalyzed by the microsomal triglyceride transfer protein (MTP). The pre-VLDL par-

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“…Similarly, Kim et al report that epigallocatechin-3 gallate (EGCG)-induced COX-2 expression requires activation of p38 MAPK via PKC pathway in astrocyte and immortalized astroglial cells. 33 Acrolein levels are increased in patients with atherosclerosis as well as in cigarette smokers, 8,9 which is strongly associated with an increased risk of vascular disease in clinic. Thus increased acrolein levels might be involved in pathogenesis of atherosclerosis.…”

mentioning

confidence: 99%

Acrolein Induces Cyclooxygenase-2 and Prostaglandin Production in Human Umbilical Vein Endothelial Cells

Park

Kim

Misonou

et al. 2007

ATVB

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Objective-Acrolein, a known toxin in tobacco smoke, might be involved in atherogenesis. This study examined the effect of acrolein on expression of cyclooxygenase-2(COX-2) and prostaglandin (PG) production in endothelial cells. Methods and Results-Cyclooxygenase (COX)-2 induction by acrolein and signal pathways were measured using Western blots, Northern blots, immunoflouresence, ELISA, gene silencing, and promoter assay. Colocalization of COX2 and acrolein-adduct was determined by immunohistochemistry. Here we report that the levels of COX-2 mRNA and protein are increased in human umbilical vein endothelial cells (HUVECs) after acrolein exposure. COX-2 was found to colocalize with acrolein-lysine adducts in human atherosclerotic lesions. Inhibition of p38 MAPK activity abolished the induction of COX-2 protein and PGE 2 accumulation by acrolein, while suppression of extracellular signal-regulated kinase (ERK) and JNK activity had no effect on the induction of COX-2 expression in experiments using inhibitors and siRNA. Furthermore, rottlerin, an inhibitor of protein kinase C␦ (PKC␦), abrogated the upregulation of COX-2 at both protein and mRNA levels. Conclusion-These results provide that acrolein may play a role in progression of atherosclerosis and new information on the signaling pathways involved in COX-2 upregulation in response to acrolein and provide evidence that PKC␦ and p38 MAPK are required for transcriptional activation of COX-2. Key Words: acrolein Ⅲ COX-2 Ⅲ p38 MAPK Ⅲ atherosclerosis Ⅲ endothelial cells A ctivation of endothelial cells by proinflammatory stimuli has been established as an important link between risk factors and the pathologic mechanisms underlying atherosclerosis. 1 Thus, control of the inflammatory status of endothelial cells, which is achieved by a balance of pro-and antiinflammatory signals, is crucial to limiting the disease. Tobacco smoking induces inflammatory reactions 2 and promotes atherosclerosis 3 ; however, the mechanism that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood.Acrolein (CH 2 ϭCH-CHO), a major product of organic combustion, including tobacco smoking, is the most reactive ␣, ␤-unsaturated aldehyde found widely in the environmol/ Lent. Acrolein is highly reactive and is hazardous to human health. 4 Acrolein is produced by a wide variety of both natural and synthetic processes, including the incomplete combustion of organic materials. Acrolein also has been found to be formed from threonine by neutrophil myeloperoxidase at sites of inflammation 5 and has been identified as both a product and initiator of lipid peroxidation. 6 Recent studies have shown that acrolein levels are increased in many diseases such as atherosclerosis, Alzheimer disease, and diabetes, and is possibly related to pathogenesis in these conditions. 7-9 We and others have reported that acrolein elevates intracellular reactive oxygen species (ROS) levels, which leads to cell dysfunction. 8,10 ROS-mediated cell damage is an important etiologic factor ...

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Phospholipase D Isozymes Mediate Epigallocatechin Gallate-induced Cyclooxygenase-2 Expression in Astrocyte Cells

Cited by 39 publications

References 54 publications

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Protease-Activated Receptors Differentially Regulate Human Platelet Activation through a Phosphatidic Acid-Dependent Pathway

Epigallocatechin gallate increases the formation of cytosolic lipid droplets and decreases the secretion of apoB-100 VLDL

Acrolein Induces Cyclooxygenase-2 and Prostaglandin Production in Human Umbilical Vein Endothelial Cells

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