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01-05-2009 | ORIGINAL CONTRIBUTION

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Authors: Catherine Gebhard, MD, Simon F. Stämpfli, MD, Caroline E. Gebhard, Alexander Akhmedov, PhD, Alexander Breitenstein, MD, Giovanni G. Camici, PhD, Erik W. Holy, MD, Thomas F. Lüscher, MD, Felix C. Tanner, MD

Published in: Basic Research in Cardiology | Issue 3/2009

Abstract

Background

The phytosterol guggulsterone is a potent anti-inflammatory mediator with less side effects than classic steroids. This study assesses the impact of guggulsterone on tissue factor (TF) expression and thrombus formation.

Methods and results

Guggulsterone inhibited TNF-α-induced endothelial TF protein expression and surface activity in a concentration-dependent manner; in contrast, dexamethasone did not affect TNF-α-induced TF expression. Guggulsterone enhanced endothelial tissue factor pathway inhibitor and impaired plasminogen activator inhibitor-1 as well as vascular cell adhesion molecule-1 protein. Real-time polymerase chain reaction revealed that guggulsterone inhibited TNF-α-induced TF mRNA expression; moreover, it impaired activation of the MAP kinases JNK and p38, while that of ERK remained unaffected. In vivo, guggulsterone inhibited TF activity and photochemical injury induced thrombotic occlusion of mouse carotid artery. Guggulsterone also inhibited TF expression, proliferation, and migration of vascular smooth muscle cells in a concentration-dependent manner.

Conclusions

Guggulsterone inhibits TF expression in vascular cells as well as thrombus formation in vivo; moreover, it impairs vascular smooth muscle cell activation. Hence, this phytosterol offers novel therapeutic options, in particular in inflammatory diseases associated with an increased risk of thrombosis.

Agarwal RC, Singh SP, Saran RK, Das SK, Sinha N, Asthana OP, Gupta PP, Nityanand S, Dhawan BN, Agarwal SS (1986) Clinical trial of gugulipid—a new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 84:626PubMed

Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F (1988) Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Br Heart J 59:535PubMedCrossRef

Baldwa VS, Bhasin V, Ranka PC, Mathur KM (1981) Effects of Commiphora mukul (Guggul) in experimentally induced hyperlipemia and atherosclerosis. J Assoc Physicians India 29:13PubMed

Bishop-Bailey D (2004) FXR as a novel therapeutic target for vascular disease. Drug News Perspect 17:499PubMedCrossRef

Camici GG, Steffel J, Akhmedov A, Schafer N, Baldinger J, Schulz U, Shojaati K, Matter CM, Yang Z, Luscher TF, Tanner FC (2006) Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 114:1512–1521PubMedCrossRef

Crawley JT, Lane DA (2008) The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 28:233PubMedCrossRef

Day SM, Reeve JL, Pedersen B, Farris DM, Myers DD, Im M, Wakefield TW, Mackman N, Fay WP (2005) Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 105:192PubMedCrossRef

Eitzman DT, Bodary PF, Shen Y, Khairallah CG, Wild SR, Abe A, Shaffer-Hartman J, Shayman JA (2003) Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol 14:298PubMedCrossRef

Gaur SPS, Garg RK, Kar AM, Purohit JK, Gupta A (1997) Gugulipd,a new hypolipidaemic agent, in patients of acute ischaemic stroke: effect on clinical outcome, platelet function and serum lipids. Asia Pac J Pharmacol 12:65–69

10.

Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B (1987) Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 2:3PubMedCrossRef

11.

He F, Li J, Mu Y, Kuruba R, Ma Z, Wilson A, Alber S, Jiang Y, Stevens T, Watkins S, Pitt B, Xie W, Li S (2006) Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. Circ Res 98:192PubMedCrossRef

12.

Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG (1996) Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 94:2057PubMed

13.

Kalsch T, Elmas E, Nguyen XD, Suvajac N, Kluter H, Borggrefe M, Dempfle CE (2007) Endotoxin-induced effects on platelets and monocytes in an in vivo model of inflammation. Basic Res Cardiol 102:460PubMedCrossRef

14.

Khanna D, Sethi G, Ahn KS, Pandey MK, Kunnumakkara AB, Sung B, Aggarwal A, Aggarwal BB (2007) Natural products as a gold mine for arthritis treatment. Curr Opin Pharmacol 7:344PubMedCrossRef

15.

Langer HF, Gawaz M (2008) Platelets in regenerative medicine. Basic Res Cardiol 103:299PubMedCrossRef

16.

Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109:2698PubMedCrossRef

17.

Li YT, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D (2007) Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol 27:2606PubMedCrossRef

18.

Luyendyk JP, Piper JD, Tencati M, Reddy KV, Holscher T, Zhang R, Luchoomun J, Chen X, Min W, Kunsch C, Mackman N (2007) A novel class of antioxidants inhibit LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases. Arterioscler Thromb Vasc Biol 27:1857PubMedCrossRef

19.

Maier W, Altwegg LA, Corti R, Gay S, Hersberger M, Maly FE, Sutsch G, Roffi M, Neidhart M, Eberli FR, Tanner FC, Gobbi S, von Eckardstein A, Luscher TF (2005) Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein. Circulation 111:1355PubMedCrossRef

20.

Ott I, Michaelis C, Schuermann M, Steppich B, Seitz I, Dewerchin M, Zohlnhofer D, Wessely R, Rudelius M, Schomig A, Carmeliet P (2005) Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor. Circ Res 97:293PubMedCrossRef

21.

Pandolfi A, Giaccari A, Cilli C, Alberta MM, Morviducci L, De Filippis EA, Buongiorno A, Pellegrini G, Capani F, Consoli A (2001) Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol 38:71PubMedCrossRef

22.

Shishodia S, Aggarwal BB (2004) Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem 279:47148PubMedCrossRef

23.

Singh RB, Niaz MA, Ghosh S (1994) Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 8:659PubMedCrossRef

24.

Stahli BE, Camici GG, Steffel J, Akhmedov A, Shojaati K, Graber M, Luscher TF, Tanner FC (2006) Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation. Circ Res 99:149PubMedCrossRef

25.

Steffel J, Akhmedov A, Greutert H, Luscher TF, Tanner FC (2005) Histamine induces tissue factor expression: implications for acute coronary syndromes. Circulation 112:341PubMedCrossRef

26.

Steffel J, Hermann M, Greutert H, Gay S, Luscher TF, Ruschitzka F, Tanner FC (2005) Celecoxib decreases endothelial tissue factor expression through inhibition of c-Jun terminal NH2 kinase phosphorylation. Circulation 111:1685PubMedCrossRef

27.

Steffel J, Latini RA, Akhmedov A, Zimmermann D, Zimmerling P, Luscher TF, Tanner FC (2005) Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design. Circulation 112:2002PubMedCrossRef

28.

Steffel J, Luscher TF, Tanner FC (2006) Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 113:722PubMedCrossRef

29.

Szapary PO, Wolfe ML, Bloedon LT, Cucchiara AJ, DerMarderosian AH, Cirigliano MD, Rader DJ (2003) Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 290:765PubMedCrossRef

30.

Tilley R, Mackman N (2006) Tissue factor in hemostasis and thrombosis. Semin Thromb Hemost 32:5PubMedCrossRef

31.

Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ (1997) Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95:594PubMed

32.

True AL, Olive M, Boehm M, San H, Westrick RJ, Raghavachari N, Xu X, Lynn EG, Sack MN, Munson PJ, Gladwin MT, Nabel EG (2007) Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circ Res 101:893PubMedCrossRef

33.

Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ, Moore DD (2002) A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296:1703PubMedCrossRef

34.

Urizar NL, Moore DD (2003) GUGULIPID: a natural cholesterol-lowering agent. Annu Rev Nutr 23:303PubMedCrossRef

35.

van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ES, Tak PP (2008) Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford) 47:3CrossRef

36.

Verma N, Singh SK, Gupta RC (1999) Pharmacokinetics of guggulsterone after intravenous and oral administration in rats. Pharm Pharmacol Comm 5:349

37.

Wang X, Greilberger J, Ledinski G, Kager G, Paigen B, Jurgens G (2004) The hypolipidemic natural product Commiphora mukul and its component guggulsterone inhibit oxidative modification of LDL. Atherosclerosis 172:239PubMedCrossRef

Title: Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis
Authors: Catherine Gebhard, MD
Simon F. Stämpfli, MD
Caroline E. Gebhard
Alexander Akhmedov, PhD
Alexander Breitenstein, MD
Giovanni G. Camici, PhD
Erik W. Holy, MD
Thomas F. Lüscher, MD
Felix C. Tanner, MD
Publication date: 01-05-2009
Publisher: Steinkopff-Verlag
Published in: Basic Research in Cardiology / Issue 3/2009
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-008-0757-5

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