The pharmacological characteristics of tranilast (N(3,4dimethoxycinnamoyl)-anthranilic acid) were first described as early as the 1970s . The drug was initially introduced for the treatment of dermatological disorders such as hypertrophic scar formation and keloid [2,3]. Because of its ability to suppress mast cell degranulation and histamine release, tranilast is also used in allergic diseases such as allergic rhinitis, atopic dermatitis and asthma bronchiale [4–6].
In recent years, the effects of tranilast have been investigated in different models both in vitro and in vivo. There are a number of results indicating beneficial effects of tranilast in disorders involving matrix deposition and fibrosis.
Those effects appear to be caused by several mechanisms: (i) inhibition of matrix protein synthesis (e.g. collagen); (ii) reduction of cell proliferation (e.g. fibroblasts and smooth muscle cells); and (iii) inhibition of inflammatory responses that result in fibrosis
Tumour growth factor (TGF)β1 is known to play an important role for the synthesis of matrix proteins and cardiac fibrosis . In cell culture experiments, tranilast inhibits the TGFβ1-mediated synthesis of collagen [2,8]. The expression of TGFβ1 mRNA decreased after tranilast treatment in vitro and in vivo [8–10]. Additionally, mRNA for the type 2 TGFβ1-receptor is reduced by tranilast . Another in vivo model of fibrosis with high clinical relevance is diabetic nephropathy. Mifsud et al.  treated diabetic rats in the phase of established kidney disease and found a strong reduction of tubulointerstitial fibrosis, tubular atrophy and a near normalization of albuminuria.
Anti-proliferative effects of tranilast have been demonstrated in cardiac fibroblasts, vascular smooth muscle cells [13–16] and even in mouse lung cancer cells . Noguchi et al.  described reduction of tumour growth in a model of squamous carcinoma in vivo. The anti-proliferative effect in vivo may be at least partly attributed to inhibition of tumour angiogenesis . On the other hand, tranilast also induces the tumour suppressor gene p53 .
The pathways of the anti-fibrotic and anti-proliferative effects are incompletely understood. A microfibril- associated glycoprotein has been identified as a possible target of tranilast . Growth inhibition of vascular smooth muscle cells appears to be mediated by inhibition of platelet-derived growth factor homodimer-BB receptor binding . There is also evidence that tranilast suspends the cell cycle of fibroblasts at the G0/G1 phase. Tranilast induces the cyclin-dependent kinase (CDK) inhibitor p21 which suppresses CDK2 and CDK4 activity and thus inhibits proliferation [15,20].
Several clinical studies involving humans have been performed. In a recent pilot study in humans with advanced diabetic nephropathy, tranilast was reported to slow the decline in glomerular filtration rate over a 12-month period . Because tranilast combines anti-fibrotic and growth-inhibiting properties, it appeared provocative to evaluate its possible effects on the prevention of neointima formation and restenosis after coronary artery dilatation. After promising results were obtained from animal experiments [10,24,25] and preliminary clinical studies (TREAT 1 and 2) , the large PRESTO trial (involving more than 10 000 patients) had to be cancelled ahead of schedule because no beneficial effect of tranilast could be found . At a high price, we have learned once more that hypotheses arising from cell culture and animal experiments do not necessarily correspond to large-scale clinical settings in humans.
In addition to anti-proliferative and anti-fibrotic effects, an anti-inflammatory potency of tranilast (apart from mast-cell stabilization) is discussed but the relevant mechanisms remain poorly understood. Capper et al.  demonstrated an inhibition of pro-inflammatory activity of monocytes after incubation with tranilast. Inhibition of interleukin (IL)-1β-induced expression of the monocyte chemo-attractant peptide (MCP)-1 was reported . Tranilast also prevents leukocyte accumulation around porcine coronary arteries after stenting .
Recent cell culture experiments investigated the molecular mechanisms of anti-inflammatory tranilast action. In human umbilical vein endothelial cells the effects of tranilast on the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) were investigated . NF-κB is essential for the induction of numerous pro-inflammatory genes such as endothelial cell adhesion molecules, namely intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and cytokines (e.g. TNFα and -β, interleukin-2, -6 and -8) [31,32]. Expression of ICAM-1, VCAM-1 and E-selectin mediate the adhesion of monocytes, lymphocytes and granulocytes to the vascular endothelium and thus play an important role for inflammatory processes . TNFα-induced expression of endothelial VCAM-1, ICAM-1 and E-selectin, and the secretion of IL-6 is dose-dependently inhibited by tranilast whereas NF-κB independent processes remain unchanged. Moreover, the expression of the transcriptional coactivator CBP (cAMP response element binding protein binding protein) is inhibited by tranilast, resulting in a loss of interaction between NF-κB and CBP. It is therefore suggested that tranilast inhibits the expression of adhesion molecules via inhibition of the interaction between NF-κB and its transcriptional coactivator CBP .
Hypertensive heart disease entails structural remodelling of cardiomyocyte and non-myocyte cells. This remodelling involves an inflammatory component mediated by adhesion molecules [34,35]. Transcriptional activation of the genes of those molecules is tightly regulated by NF-κB. Consecutive monocyte/macrophage infiltration and activation results in activation of the renin–angiotensin–aldosterone system (RAS) and synthesis of TGFβ1 . Inhibitors of the RAS are well known to attenuate cardiac remodelling [16,37]. Angiotensin II itself, which is primarily activated in many hypertensive mouse models, is known to induce TGFβ1 in different cardiac cells [38,39]. TGFβ1 directly stimulates the formation of extracellular matrix including collagen (type I and III) and also blocks extracellular matrix degradation by stimulating protease inhibitors, including platelet activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase (TIMP) . The excess of ventricular collagen partly results from insufficient collagen degradation by interstitial collagenases and metalloproteinases (MMPs), whose activity is regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Finally, the fibrosis results in progressive abnormalities of diastolic ventricular filling and relaxation, systolic dysfunction and conduction disturbances, thus contributing to the clinical risk associated with left ventricular hypertrophy. Cardiac fibrosis is recognized as a key process in the progression from compensated cardiac hypertrophy to cardiac dysfunction and heart failure . Of course, this suggested line of events is oversimplified and many other factors are involved in the pathogenesis of hypertensive heart disease .
In deoxycorticosterone acetate (DOCA) salt-sensitive hypertensive rats, the cardiac inflammatory response was recently analysed . It was demonstrated that NF-κB, VCAM-1, the platelet-endothelial cell adhesion molecule-1 and MMPs are upregulated in the heart of DOCA-salt rats. However, NF-κB decoy oligodeoxynucleotides were unable to reduce gene expression of TGFβ1 and fibrosis in a model of nitro-l-arginine methyl ester-induced cardiac fibrosis , suggesting the existence of an additional NF-κB-independent pathway for cardiac fibrosis. This is supported by the finding that collagen is already upregulated after 1 week of DOCA-salt treatment whereas NF-κB binding activity rose only after the second week . In another model of mineralocorticoid-induced hypertension, the time course of cardiac fibrosis development was described. Interestingly, the first change to be noted was a significantly elevated immunohistochemical level of collagen III . The fact that blood pressure is not yet significantly elevated at that time supports previous findings that the origin of cardiac fibrosis is humoral rather than haemodynamic, whereas cardiomyocyte hypertrophy is clearly associated to hypertension .
There are two studies performed in vivo showing that tranilast is capable of suppressing myocardial fibrosis in hypertensive animals. The study by Pinto et al.  compared tranilast to losartan in hypertensive TGR (mRen2)27 rats, a transgenic rat model characterized by increased cardiac angiotensin II concentrations . Both drugs prevented the increase in left ventricular TGFβ1 mRNA, collagen accumulation and left ventricular hypertrophy without lowering blood pressure. Moreover, even a significant positive effect on survival was seen after treatment with tranilast. The second study was designed to investigate whether tranilast would also inhibit collagen accumulation in a rat model of renovascular hypertension (Goldblatt two-kidney, one-clip model). In accordance with the previous study, a preventive effect on cardiac fibrosis was shown .
In this issue of the journal, Kagitani et al.  evaluated tranilast effects in DOCA-salt hypertensive rats. In its approach, the study goes beyond previous studies, focusing on anti-inflammatory aspects of tranilast action in the course of cardiac fibrosis development. In comparison to previous studies, only one-quarter of the tranilast dose was used (100 mg/kg per day). The study confirms that inflammatory processes are involved in fibrosis development in this model. Apart from increased expression of TGFβ1, PAI-1 and collagen accumulation the presence of the inflammation-related peptides MCP-1 and IL-6 is detected. For the first time, a suppression of inflammatory processes by tranilast could be shown in vivo. MCP-1, IL-6 and monocyte/macrophage infiltration could be reduced by tranilast in a blood pressure-independent manner. Kagitani et al.  suggest that reduction of collagen synthesis and fibrosis might be a consequence of the attenuation of the inflammatory response.
This concept certainly merits further attention. It would be particularly interesting to define the effects of tranilast on the pro-inflammatory transcription factor NF-κB and related adhesion molecules that are known to be involved in the DOCA-salt model of cardiac fibrosis, and also known to be influencable by tranilast. Kagitani et al.  propose an anti-MCP-1 or MCP-1 knockout strategy to further establish the line from macrophages and inflammation to fibrosis. However, the study by Fujisawa et al.  demonstrated that part of the collagen deposition (type III) precedes inflammation, thus suggesting a second pathway independent of inflammation, possibly via direct action of angiotensin II or inflammation-independent release of TGFβ1. This finding could not be confirmed by Kagitani et al. .
Pinto et al.  and Hocher et al.  found angiotensin-converting enzyme (ACE) inhibitors (i.e. angiotensin II receptor antagonists) to be about as effective as tranilast. Apart from many other effects, blocking of the RAS also prevents the initial inflammatory cell response in models of hypertensive heart disease . A possible additive effect of tranilast combined with ACE inhibitors, angiotensin II receptor antagonists or antagonists of aldosterone remains to be evaluated, although an antagonizing effect on angiotensin II has also been described for tranilast on its own . This angiotensin II antagonizing effect of tranilast is not strong enough to cause lowering of blood pressure even at a four-fold higher dose compared to the present study [9,16].
The study by Kagitani et al.  adds another piece to the puzzle concerning pathways leading from hypertension and the activation of RAS to cardiac fibrosis. Tranilast, most likely in addition to its other pharmacological approaches, is a promising compound against fibrotic remodelling of the heart, and possibly other organs such as the kidney in diabetic nephropathy. Negative results from the first clinical studies should not discourage further research, especially because no major side-effects of tranilast have been reported to date.
1. Azuma H, Banno K, Yoshimura T. Pharmacological properties of N-(3′,4′-dimethoxycinnamoyl) anthranilic acid (N-5′), a new anti-atopic agent. Br J Pharmacol 1976; 58:483–488.
2. Suzawa H, Kikuchi S, Arai N, Koda A. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol 1992; 60:91–96.
3. Shigeki S, Murakami T, Yata N, Ikuta Y. Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast. Scand J Plast Reconstr Surg Hand Surg 1997; 31:151–158.
4. Koda A, Kurashina Y, Nakazawa M. The inhibition mechanism of histamine release by N-(3,4-dimethoxycinnamoyl) anthranilic acid. Int Arch Allergy Appl Immunol 1985; 77:244–245.
5. Shioda H. A double blind controlled trial of N-(3′, 4′-dimethoxycinnamoyl) anthranilic acid on children with bronchial asthma. N-5′ Study Group in Children. Allergy 1979; 34:213–219.
6. Okuda M, Ishikawa T, Saito Y, Shimizu T, Baba S. A clinical evaluation of N-5′ with perennial-type allergic rhinitis – a test by the multi-clinic, intergroup, double-blind comparative method. Ann Allergy 1984; 53: 178–185.
7. Kuwahara F, Kai H, Tokuda K, Kai M, Takeshita A, Egashira K, Imaizumi T. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction, in pressure-overloaded rats. Circulation 2002; 106:130–135.
8. Ikeda H, Inao M, Fujiwara K. Inhibitory effect of tranilast on activation and transforming growth factor beta 1 expression in cultured rat stellate cells. Biochem Biophys Res Commun 1996; 227:322–327.
9. Pinto YM, Pinto-Sietsma SJ, Philipp T, Engler S, Kossamehl P, Hocher B, et al. Reduction in left ventricular messenger RNA for transforming growth factor beta(1) attenuates left ventricular fibrosis and improves survival without lowering blood pressure in the hypertensive TGR (mRen2)27 rat. Hypertension 2000; 36:747–754.
10. Ward MR, Agrotis A, Kanellakis P, Hall J, Jennings G, Bobik A. Tranilast prevents activation of transforming growth factor-beta system, leukocyte accumulation, and neointimal growth in porcine coronary arteries after stenting. Arterioscler Thromb Vasc Biol 2002; 22:940–948.
11. Ward MR, Sasahara T, Agrotis A, Dilley RJ, Jennings GL, Bobik A. Inhibitory effects of tranilast on expression of transforming growth factor-beta isoforms and receptors in injured arteries. Atherosclerosis 1998; 137:267–275.
12. Mifsud S, Kelly DJ, Qi W, Zhang Y, Pollock CA, Wilkinson-Berka JL, Gilbert RE. Intervention with tranilast attenuates renal pathology and albuminuria in advanced experimental diabetic nephropathy. Nephron Physiol 2003; 95:83–91.
13. Miyazawa K, Hamano S, Ujiie A. Antiproliferative and c-myc mRNA suppressive effect of tranilast on newborn human vascular smooth muscle cells in culture. Br J Pharmacol 1996; 118:915–922.
14. Fukuyama J, Ichikawa K, Miyazawa K, Hamano S, Shibata N, Ujiie A. Tranilast suppresses intimal hyperplasia in the balloon injury model and cuff treatment model in rabbits. Jpn J Pharmacol 1996; 70:321–327.
15. Takahashi A, Taniguchi T, Ishikawa Y, Yokoyama M. Tranilast inhibits vascular smooth muscle cell growth and intimal hyperplasia by induction of p. 21 (waf1/cip1/sdi1) and p53. Circ Res 1999; 84:543–550.
16. Hocher B, Godes M, Olivier J, Weil J, Eschenhagen T, Slowinski T, et al. Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension. J Hypertens 2002; 20:745–751.
17. Yatsunami J, Aoki S, Fukuno Y, Kikuchi Y, Kawashima M, Hayashi SI. Antiangiogenic and antitumor effects of tranilast on mouse lung carcinoma cells. Int J Oncol 2000; 17:1151–1156.
18. Noguchi N, Kawashiri S, Tanaka A, Kato K, Nakaya H. Effects of fibroblast growth inhibitor on proliferation and metastasis of oral squamous cell carcinoma. Oral Oncol 2003; 39:240–247.
19. Isaji M, Miyata H, Ajisawa Y, Takehana Y, Yoshimura N. Tranilast inhibits the proliferation, chemotaxis and tube formation of human microvascular endothelial cells in vitro and angiogenesis in vivo. Br J Pharmacol 1997; 122:1061–1066.
20. Shime H, Kariya M, Orii A, Momma C, Kanamori T, Fukuhara K, Kusakari T, et al. Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21 (waf1) and p53. J Clin Endocrinol Metab 2002; 87:5610–5617.
21. Furuichi H, Yamashita K, Okada M, Toyoshima T, Hata Y, Suzuki S, et al. Identification of tranilast-binding protein as 36-kDa microfibril-associated glycoprotein by drug affinity chromatography, and its localization in human skin. Biochem Biophys Res Commun 2000; 270:1002–1008.
22. Watanabe S, Matsuda A, Suzuki Y, Kondo K, Ikeda Y, Hashimoto H, Umemura K. Inhibitory mechanism of tranilast in human coronary artery smooth muscle cells proliferation, due to blockade of PDGF-BB-receptors. Br J Pharmacol 2000; 130:307–314.
23. Soma J, Sugawara T, Huang YD, Nakajima J, Kawamura M. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 2002; 92:693–698.
24. Ishiwata S, Verheye S, Robinson KA, Salame MY, de Leon H, King SB, III, Chronos NA. Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation. J Am Coll Cardiol 2000; 35:1331–1337.
25. Shiota N, Okunishi H, Takai S, Mikoshiba I, Sakonjo H, Shibata N, Miyazaki M. Tranilast suppresses vascular chymase expression and neointima formation in balloon-injured dog carotid artery. Circulation 1999; 99:1084–1090.
26. Tamai H, Katoh K, Yamaguchi T, Hayakawa H, Kanmatsuse K, Haze K, et al. The impact of tranilast on restenosis after coronary angioplasty: the Second Tranilast Restenosis Following Angioplasty Trial (TREAT-2). Am Heart J 2002; 143:506–513.
27. Holmes DR Jr, Savage M, LaBlanche JM, Grip L, Serruys PW, Fitzgerald P, et al. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2002; 106:1243–1250.
28. Capper EA, Roshak AK, Bolognese BJ, Podolin PL, Smith T, Dewitt DL, et al. Modulation of human monocyte activities by tranilast, SB 252218, a compound demonstrating efficacy in restenosis. J Pharmacol Exp Ther 2000; 295:1061–1069.
29. Chikaraishi A, Hirahashi J, Takase O, Marumo T, Hishikawa K, Hayashi M, Saruta T. Tranilast inhibits interleukin-1beta-induced monocyte chemoattractant protein-1 expression in rat mesangial cells. Eur J Pharmacol 2001; 427:151–158.
30. Spiecker M, Lorenz I, Marx N, Darius H. Tranilast inhibits cytokine-induced nuclear factor kappaB activation in vascular endothelial cells. Mol Pharmacol 2002; 62:856–863.
31. Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995; 9:899–909.
32. May MJ, Ghosh S. Signal transduction through NF-kappa B. Immunol Today 1998; 19:80–88.
33. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346:425–434.
34. Tomita H, Egashira K, Kubo-Inoue M, Usui M, Koyanagi M, Shimokawa H, et al. Inhibition of NO synthesis induces inflammatory changes and monocyte chemoattractant protein-1 expression in rat hearts and vessels. Arterioscler Thromb Vasc Biol 1998; 18:1456–1464.
35. Hinglais N, Heudes D, Nicoletti A, Mandet C, Laurent M, Bariety J, Michel JB. Colocalization of myocardial fibrosis and inflammatory cells in rats. Lab Invest 1994; 70:286–294.
36. Koyanagi M, Egashira K, Kubo-Inoue M, Usui M, Kitamoto S, Tomita H, et al. Role of transforming growth factor-beta1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis. Hypertension 2000; 35:86–90.
37. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709–717.
38. Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 1997; 29:1947–1958.
39. Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi M, Katoh M, et al. Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 1998; 32:273–279.
40. Laiho M, Saksela O, Keski-Oja J. Transforming growth factor-beta induction of type-1 plasminogen activator inhibitor. Pericellular deposition and sensitivity to exogenous urokinase. J Biol Chem 1987; 262: 17467–17474.
41. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322:1561–1566.
42. Weber KT. Fibrosis and hypertensive heart disease. Curr Opin Cardiol 2000; 15:264–272.
43. Ammarguellat FZ, Gannon PO, Amiri F, Schiffrin EL. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: role of ET(A) receptors. Hypertension 2002; 39:679–684.
44. Kitamoto S, Egashira K, Kataoka C, Koyanagi M, Katoh M, Shimokawa H, et al. Increased activity of nuclear factor-kappaB participates in cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis in rats. Circulation 2000; 102:806–812.
45. Fujisawa G, Dilley R, Fullerton MJ, Funder JW. Experimental cardiac fibrosis: differential time course of responses to mineralocorticoid-salt administration. Endocrinology 2001; 142:3625–3631.
46. Ohta K, Kim S, Wanibuchi H, Ganten D, Iwao H. Contribution of local renin-angiotensin system to cardiac hypertrophy, phenotypic modulation, and remodeling in TGR (mRen2)27 transgenic rats. Circulation 1996; 94:785–791.
47. Kagitani S, Ueno H, Hirade S, Takahashi T, Takata M, Inoue H. Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/salt hypertensive rats. J Hypertens 2004; 22:1007–1015.
48. Usui M, Egashira K, Tomita H, Koyanagi M, Katoh M, Shimokawa H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation 2000; 101:305–310.
49. Jin D, Takai S, Shiota N, Miyazaki M. Tranilast, an anti-allergic drug, possesses antagonistic potency to angiotensin II. Eur J Pharmacol 1998; 361:199–205.
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