nach oben

Erschienen in:

01.09.2005 | Experimental

Pretreatment with peroxysome proliferator-activated receptor α agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxin-induced shock

verfasst von: Eric Wiel, Gilles Lebuffe, Emmanuel Robin, Gaëlle Gasan, Delphine Corseaux, Benoît Tavernier, Brigitte Jude, Régis Bordet, Benoît Vallet

Erschienen in: Intensive Care Medicine | Ausgabe 9/2005

Einloggen, um Zugang zu erhalten

Abstract

Objective

To investigate the effects of fenofibrate, an activator of peroxysome proliferator activated receptor (PPAR) α, on vascular endothelium and on hemostasis in a rabbit endotoxic shock model.

Design and setting

Prospective laboratory study in a university laboratory.

Subjects

36 male New Zealand rabbits weighing 2.5–3 kg.

Interventions

We determined in vitro vascular reactivity, endothelium CD31–platelet/endothelial cell adhesion molecule (PECAM) 1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor expression 5 days after onset of endotoxic shock (0.5 mg/kg intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by fenofibrate (mixed in the chow at a concentration of 0.5%) for 15 days before lipopolysaccharide injection and 5 days afterward.

Measurements and results

Metabolic acidosis and coagulation activation confirmed presence of shock. Fenofibrate decreased monocyte tissue factor expression. It improved endothelial-dependent relaxation at 5 days (Emax=68.2±3.3%, vs. 44.2±2.5% in the non-treated group). Endotoxin-induced deendothelialization was significantly decreased by fenofibrate at 5 days (8.5±1.3% vs. 19.2±3.1% in the nontreated group).

Conclusions

These data indicate for the first time that fenofibrate, an activator of PPAR-α, inhibits monocyte tissue factor expression and protects against endothelial dysfunction and histological injury in endotoxin-induced shock.

Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150CrossRefPubMed

Kang YH. Williams R (1991) Endotoxin-induced endothelial injury and subendothelial accumulation of fibronectin in rat aorta. Anat Rec 229:86–102CrossRefPubMed

Young JS, Headrick JP, Berne RM (1991) Endothelial-dependent and -independent responses in the thoracic aorta during endotoxic shock. Circ Shock 35:25–30PubMed

Parker JL, Adams HR (1993) Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. Circ Res 72:539–551PubMed

Reidy MA, Bowyer DE (1977) Scanning electron microscopy: morphology of aortic endothelium following injury by endotoxin and during subsequent repair. Atherosclerosis 26:319–328PubMed

Lee M, Schuessler G, Chien S (1988) Time dependent effects of endotoxin on the ultrastructure of the aortic endothelium. Artery 15:71–89PubMed

Leclerc J, Pu Q, Corseaux D, Haddad E, Decoene C, Bordet R, Six I, Jude B, Vallet B (2000) A single endotoxin injection in rabbit causes prolonged blood vessel dysfunctions and procoagulant state. Crit Care Med 28:3672–3678CrossRefPubMed

Mangelsdorf DJ, Thummel C, Beato M, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839CrossRefPubMed

Isseman I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxysome proliferators. Nature 347:645–650CrossRefPubMed

10.

Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL, Green S (1992) The mouse peroxysome proliferator-activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl coA oxidase gene. EMBO J 11:433–439PubMed

11.

Rival Y, Beneteau N, Taillandier T, Pezet M, Dupont-Passelaigue E, Patoiseau JF, Junquero D, Colpaert FC, Delhon A (2002) PPAR alpha and PPAR delta activators inhibit cyokine-induced nuclear translocation of NF-kappaB and expression of VCAM-1 in EAhy926 endothelial cells. Eur J Pharmacol 435:143–151CrossRefPubMed

12.

Staels B, Koenig W, Habib A, Merval R, Lebret M, Pineda Torra I, Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf j, Tedgui A (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393:790–793CrossRefPubMed

13.

Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum JL, Auwerx J, Palinski W, Glass CK (1998) Expression of peroxysome proliferator activated receptor gamma (PPAR gamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 95:7614–7619CrossRefPubMed

14.

Duez H, Chao Y-S, Hernandez M, Torpier G, Poulain P, Mundt S, Mallat Z, Teissier E, Burton CA, Tedgui A, Fruchart JC, Fievet C, Wright SD, Staels B (2002) Reduction of atherosclerosis by the peroxysome proliferator-activated receptor α agonist fenofibrate in mice. J Biol Chem 50:48051–48057CrossRef

15.

Deplanque D, Gele P, Petrault O, Six I, Furman C, Bouly M, Nion S, Dupuis B, Leys D, Fruchart JC, Cecchelli R, Staels B, Duriez P, Bordet R (2003) Peroxysome proliferator-activated receptor-alpha activation: mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 23:6264–6271PubMed

16.

Tabernero A, Schoonjans K, Jesel L, Carpusca I, Auwerx J, Andraintsitohaina R (2002) Activation of the peroxysome proliferator-activated receptor a protects against myocardial ischaemic injury and improves endothelial vasodilation. BMC Pharmacol 2:10CrossRefPubMed

17.

Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxysome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94:4312–4317CrossRefPubMed

18.

Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98:2088–2093PubMed

19.

Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B (1999) PPARα negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J Biol Chem 274:32048–32054CrossRefPubMed

20.

Madej A, Okopien B, Kowalski J, Zielinski M, Wysocki J, Szygula B, Kalina Z, Herman ZS (1998) Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis, hyperlipoproteinemia IIb. Int J Clin Pharmacol Ther 36:345–349PubMed

21.

Neve BP, Corseaux D, Chinetti G, Zawadzki C, Fruchart JC, Duriez P, Staels B, Jude B (2001) PPARα agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation 103:207–212PubMed

22.

Wiel E, Pu Q, Corseaux D, Robin E, Bordet R, Lund N, Jude B, Vallet B (2000) Effect of L-arginine on endothelial injury and hemostasis in rabbit endotoxin shock. J Appl Physiol 89:1811–1818PubMed

23.

Pu Q, Wiel E, Corseaux D, Bordet R, Azrin MA, Ezekowitz MD, Lund N, Jude B, Vallet B (2001) Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock. Crit Care Med 29:1181–1188CrossRefPubMed

24.

Wiel E, Pu Q, Leclerc J, Corseaux D, Bordet R, Lund N, Jude B, Vallet B (2004) Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial injury, hemostasis in rabbit endotoxic shock. Intensive Care Med 30:1652–1659CrossRefPubMed

25.

Hennuyer N, Poulain P, Madsen L, Berge RK, Houdebine LM, Branellec D, Fruchart JC, Fievet C, Duverger N, Staels B (1999) Beneficial effects of fibrates on apolipoprotein A-I metabolism occur independently of any peroxysome proliferative response. Circulation 99:2445–2451PubMed

26.

Staels B, van Tol A, Andreu T, Auwerx J (1992) Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat. Arterioscler Thromb 12:286–294PubMed

27.

Hamon M, Vallet B, Bauters C, Wernert N, McFadden EP, Lablanche JM, Dupuis B, Bertrand ME (1994) Long-term oral administration of L-arginine reduces intimal thickening and enhances neo-endothelium-dependent acetylcholine-induced relaxation after arterial injury. Circulation 90:1357–1362PubMed

28.

Carson S (1987) Continuous chromogenic tissue factor assay: comparison to clot-based assays and sensitivity established using pure tissue factor. Thromb Res 47:379–387CrossRefPubMed

29.

Corseaux D, Le Tourneau T, Six I, Ezekowitz MD, McFadden EP, Meurice T, Asseman P, Bauters C, Jude B (1998) Enhanced monocyte tissue factor response after experimental balloon angioplasty in hypercholesterolemic rabbit: inhibition with dietary L-arginine. Circulation 98:1776–1782PubMed

30.

Taylor FB Jr, Wada H, Kinasewitz G (2000) Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC. Crit Care Med 28 [Suppl 9]:S12–S19

31.

Erlich J, Fearns C, Mathison J, Ulevitch RJ, Mackman N (1999) Lipopolysaccharide induction of tissue factor expression in rabbits. Infect Immun 67:2540–2546PubMed

32.

Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Mareyy A, Lestavel P (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816–823PubMed

33.

Hall AJ, Vos HL, Bertina RM (1999) Lipopolysaccharide induction of tissue factor in THP-1 cells involves Jun protein phosphorylation, nuclear factor κB nuclear translocation. J Biol Chem 274:376–383CrossRefPubMed

34.

Wu R, Xu Y, Song X, Meng X (2002) Gene expression of adhesion molecules in pulmonary and hepatic microvascular endothelial cells during sepsis. Chin J Traumatol 5:146–150PubMed

35.

Delerive P, Gervois P, Fruchart JC, Staels B (2000) Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxysome proliferator-activated receptor-α activators. J Biol Chem 47:36703–36707CrossRef

36.

Van Oosten M, van de Bilt E, de Vries HE, van Berkel TJ, Kuiper J (1997) Vascular adhesion molecule-1 and intercellular molecule expression on rat liver cells after lipopolysaccharide administration in vivo. Hepatology 25:1538–1546

37.

Marx N, Sukhova G, Collins T, Libby P, Plutzky J (1999) PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99:3125–3131PubMed

38.

Lefer AM, Tsao PS, Ma XL (1991) Shock- and ischemia-induced mechanisms of impairment of endothelium-mediated vasodilation. Chest 100 [Suppl 3]:S160–S163

39.

Aoki N, Siegfried M, Lefer AM (1989) Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol 256:H1509–H1512PubMed

40.

Mügge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, Harrison DG (1991) Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res 69:1293–1300PubMed

41.

Keaney JF Jr, Xu A, Cunningham D, Jackson T, Frei B, Vita JA (1995) Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest 95:2520–2529PubMed

42.

Griendling KK, Sorescu D, Lassègue B, Ushio-Fukai M (2000) Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 20:2175–2183PubMed

43.

Yoo HY, Chang MS, Rho HM (1999) Induction of the rat Cu/Zn superoxide dismutase gene through the peroxisome proliferator-responsive element by arachidonic acid. Gene 234:87–91CrossRefPubMed

44.

Arnaiz SL, Travacio M, Llesuy S, Boveris A (1995) Hydrogen peroxide metabolism during peroxysome proliferation by fenofibrate. Biochim Biophys Acta 1272:175–180PubMed

45.

Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol 259:H1038–H1043PubMed

46.

Szabo C, Mitchell JA, Thiemermann C, Vane JR (1993) Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 108:786–792PubMed

47.

Adeagbo ASO, Triggle CR (1993) Interactions of nitric oxide synthase inhibitors and dexamethasone with α-adrenoreceptor-mediated responses in rat. Br J Pharmacol 109:495–501PubMed

48.

Goya K, Sumitani S, Xu X, Kitamura T, Yamamoto H, Kurebayashi S, Saito H, Kouhara H, Kasayama S, Kawase I (2004) Peroxysome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol 24:658–663CrossRefPubMed

49.

Naderali EK, Fatani S, Williams G (2004) Fenofibrate lowers adiposity and corrects metabolic abnormalities, but only partially restores endothelial function in dietary obese rats. Atherosclerosis 177:307–312CrossRefPubMed

50.

Ganotakis E, Tsimihodimos V, Bairaktari E, Rizos E, Athyros V, Seferiades C, Elisaf M (2002) Effects of various fibrates on serum alkaline phosphatase activity. Atherosclerosis 165:187–188CrossRefPubMed

51.

Steinmetz J, Morin C, Panek E, Siest G, Drouin P (1981) Biological variations in hyperlipidemic children and adolescents treated with fenofibrate. Clin Chim Acta 112:43–53CrossRefPubMed

52.

Papadakis JA, Ganotakis ES, Jagroop IA, Winder AF, Mikhailidis DP (1999) Statin+fibrate combination therapy: fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease. Int J Cardiol 69:237–244CrossRefPubMed

53.

Mikhailidis DP, Ganotakis ES, Spyropoulos KA, Jagroop IA, Byrne DJ, Winder AF (1998) Prothrombotic and lipoprotein variables in patients attending a cardiovascular risk management clinic: response to ciprofibrate or lifestyle advice. Int Angiol 17:225–233PubMed

54.

Krey G, Braissant O, Ehorset F, Kalkhoven E, Perroud M, Parker MG, Wahli W (1999) Fatty acids, eicosanoids and hypolipidemic agents identified as ligands of peroxysome proliferators by coactivator-dependent receptor ligand assay. Mol Endocrinol 11:779–791CrossRef

55.

Rabasa-Lhoret R, Rasamisoa M, Avignon A, Monnier L (2001) Rare side-effects of fenofibrate. Diabetes Metab 27:66–68PubMed

56.

Balfour JA, McTavish D, Heel RC (1990) Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidemia. Drugs 40:260–290PubMed

Titel: Pretreatment with peroxysome proliferator-activated receptor α agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxin-induced shock
verfasst von: Eric Wiel
Gilles Lebuffe
Emmanuel Robin
Gaëlle Gasan
Delphine Corseaux
Benoît Tavernier
Brigitte Jude
Régis Bordet
Benoît Vallet
Publikationsdatum: 01.09.2005
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 9/2005
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-005-2730-1

Update AINS

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

hier abonnieren

Springer Medizin

Pretreatment with peroxysome proliferator-activated receptor α agonist fenofibrate protects endothelium in rabbit Escherichia coli endotoxin-induced shock