Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells.

Division of Cardiology, Department of Medicine, University of California, Los Angeles, USA.
Circulation Research (Impact Factor: 11.09). 10/2000; 87(6):516-21. DOI: 10.1161/01.RES.87.6.516
Source: PubMed

ABSTRACT The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPARalpha ligand-binding domain by MM-LDL, Ox-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl-sn-glycero-phosphocholine and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine; these lipids also activated a consensus peroxisome proliferator-activated receptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPARalpha with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPARgamma agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPARalpha null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPARalpha in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.

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    ABSTRACT: Endothelium injury is a primary event in atherogenesis, which is followed by monocyte infiltration, macrophage differentiation, and smooth muscle cell migration. Peroxisome proliferator-activated receptors (PPARs) are transcription factors now recognized as important mediators in the inflammatory response. The aim of this study was to develop a human endothelial model to evaluate anti-inflammatory properties of PPAR activators. PPAR proteins (α, δ and γ) are expressed in EAhy926 endothelial cells (ECs). Pirinixic acid (Wy-14643), fenofibrate, fenofibric acid, the Merck ligand PPARδ activator L-165041, 15-deoxy-Δ12,14-prostaglandin J2, but not rosiglitazone (BRL-49653) inhibited the induced expression of vascular cell adhesion molecule-1 (VCAM-1), as measured by enzyme linked immunosorbent assay (ELISA), and monocyte binding to activated-EAhy926 cells. The PPARδ activator L-165041 had the greatest potency to reduce cytokine-induced monocyte chemotactic protein-1 (MCP-1) secretion. All PPAR activators tested which impaired VCAM-1 expression reduced significantly nuclear p65 amount. These results show that EAhy926 endothelial cells are an adequate tool to substantiate and characterize inflammatory impacts of PPAR activators.
    European Journal of Pharmacology 01/2002; 435(2). DOI:10.1016/S0014-2999(01)01589-8 · 2.68 Impact Factor
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    ABSTRACT: Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferator-activated receptor γ (PPARγ) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti-atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARγ. However, the impact of PPARγ activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARγ by thiazolidinediones induces anti-atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARγ and mediate anti-atherogenic effects through PPARγ activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti-atherogenic effects through PPARγ activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARγ, thereby mediating anti-atherogenic effects in macrophages. Therefore, statin therapy and part of anti-hypertensive therapy might produce beneficial effects through PPARγ activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARγ might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti-atherogenic effects of PPARγ and suggest potential therapeutic approaches to prevent diabetic macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00182.x, 2012).
    02/2012; 3(1):11-23. DOI:10.1111/j.2040-1124.2011.00182.x
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    ABSTRACT: BackgroundA long-term high-fat/cholesterol (HFC) diet leads to insulin resistance (IR), which is associated with inflammation, atherosclerosis (AS), cardiac sympathovagal imbalance, and cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) and nuclear factor ¿B (NF-¿B)are involved in the development of IR-AS. Thus, we elucidated the pathological molecular mechanism of IR-AS by feeding an HFC diet to Tibetan minipigs to induce IR and AS.Methods Male Tibetan minipigs were fed either a normal diet or an HFC diet for 24 weeks. Thereafter, the minipigs were tested for physiological and biochemical blood indices, blood pressure, cardiac function, glucose tolerance, heart rate variability (HRV), and PPAR-associated gene and protein expression levels.ResultsHFC-fed minipigs exhibited IR through increased body weight, fasting blood glucose levels, plasma cholesterol and its composition, and insulin and free fatty acid (FFA) levels; decreased insulin sensitivity; impaired glucose tolerance; and hypertension. Increased C-reactive protein (CRP) levels, cardiac dysfunction, depressed HRV, and the up-regulation of PPAR expression in the abdominal aorta concomitant with down-regulation in the heart tissue were observed in HFC-fed minipigs. Furthermore, the levels of NF-¿Bp65, IL-1ß, TNF-¿, MCP-1, VCAM-1, ICAM-1, MMP-9, and CRP proteins were also significantly increased.Conclusions These data suggest that HFC-fed Tibetan minipigs develop IR and AS and that PPARs are involved in cardiovascular remodeling and impaired function.
    Cardiovascular Diabetology 01/2015; 14(1):6. DOI:10.1186/s12933-014-0165-0 · 3.71 Impact Factor

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