PAI-1 and TGF-β
2006; Lippincott Williams & Wilkins; Volume: 26; Issue: 4 Linguagem: Inglês
10.1161/01.atv.0000209949.86606.c2
ISSN1524-4636
Autores Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 26, No. 4PAI-1 and TGF-β Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPAI-1 and TGF-βUnmasking the Real Driver of TGF-β–Induced Vascular Pathology Douglas E. Vaughan Douglas E. VaughanDouglas E. Vaughan From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn. Originally published1 Apr 2006https://doi.org/10.1161/01.ATV.0000209949.86606.c2Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:679–680Atherosclerosis is an extremely complex disease process in which genetic, lipid, cellular, and immunologic factors combine to determine the location, severity, and timing of lesion development and clinical events.1 With the current epidemic of obesity and the metabolic syndrome, additional factors are now recognized as contributors to the vascular disease equation, including plasminogen activator inhibitor-1 (PAI-1),2 which is one of the critical physiological regulators of plasminogen activation. PAI-1 accumulates in atherosclerotic lesions3 and contributes to a variety of vascular pathologies including coronary artery thrombosis4 and perivascular fibrosis.5,6 Numerous factors are known to regulate vascular PAI-1 production, including nitric oxide (NO), which directly suppresses PAI-1 expression.7 Simply inhibiting vascular NO production stimulates arterial PAI-1 accumulation and promotes the development of PAI-1–dependent perivascular fibrosis.8 Other factors promote vascular pathology and arteriosclerosis through mechanisms that likely involve PAI-1, including Angiotensin II9 and transforming growth factor-β1 (TGF-β1).10 The important role of TGF-β in regulating PAI-1 expression has been extensively investigated and, in fact, PAI-1 promoter constructs are widely used in reductionist studies that have defined the molecular mechanisms of TGF-β–dependent transcriptional activation and suppression.11–13See page 737Although the molecular link between TGF-β and PAI-1 is well established, the functional impact of this interaction is less well understood. Both TGF-β1 and TGF-β3 upregulate PAI-1 expression in vascular tissue at the promoter level. TGF-β family signaling is positively modulated by various members of the Smad family of signal transduction proteins, and these transcription factors bind to defined elements in the PAI-1 promoter.14 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Otsuka and colleagues explore the effects of TGF-β1 in promoting intimal growth in uninjured murine carotid arteries.15 As expected, adenoviral delivered TGF-β1 stimulates PAI-1 expression in transduced arteries, whereas the null adenoviral construct has little effect. Adenoviral-mediated overexpression of TGF-β1 promotes the accumulation of matrix-rich highly cellular intimal arterial lesions. In contrast, adenoviral TGF-β1 overexpression has modest effects on the size or the cellularity of the arterial media. Interestingly, the authors found that PAI-1–deficient mice are essentially protected from TGF-β1–induced intimal expansion, even though PAI-1 deficiency is associated with increased total and active TGF-β1 secretion after treatment with adenoviral TGF-β1. These findings correspond quite well with recent work published by Krag et al who reported that PAI-1 gene deficiency attenuates TGF-β1–induced kidney disease, by decreasing both glomerular and interstitial ECM deposition.16The authors conclude that PAI-1 is a critical mediator of TGF-β1–induced intimal growth and a key negative regulator of TGF-β1 expression in the arterial wall. These conclusions may be accurate but need to be considered in the experimental context with some important reservations. The model of intimal growth used in these studies involved uninjured mouse carotid arteries. The functional interaction between TGF-β1 and PAI-1 in diseased human vasculature undoubtedly presents a much more complex environment, and this complexity may amplify or nullify the effects reported here. The presence of other cytokines, transcriptional complexes, and cell types in an injured vessel would likely present powerful confounding effects on the relatively simple linear relationship between TGF-β1 and PAI-1 suggested by this study. In fact, at present, there is no direct evidence that TGF-β1 regulates vascular PAI-1 production in diseases associated with increased arterial PAI-1, including type 2 diabetes mellitus17 and atherosclerosis. However, this work does indicate that important and undesirable vascular effects of TGF-β1 are strongly influenced by PAI-1. This in turn adds greater momentum for the development and testing of specific PAI-1 antagonists, which have been reported to reduce the development of arteriosclerosis18 and intravascular thrombosis,19 may provide additional benefits in the treatment of arterial disease that is accelerated or influenced by local effects of TGF-β1.In Euclidean geometry, the area of a circle is defined as π×radius2 (A=πr2). Based on the findings and interactions reported here, it appears that the biological homonym PAI is a powerful determinant of intimal area in response to TGF-β1 (A&TGF-β1×PAI-1). Download figureDownload PowerPointMechanisms and effects described in the manuscript by Otsuka et al. A, Effects of adenoviral-delivered TGF-β1 treatment in wild-type (WT) mice. TGF-β1 induced intimal expansion, characterized by smooth muscle cell (SMC) migration into the area, matrix accumulation (shown in blue), induction of expression of PAI-1, and TGF-β1 production. In contrast, in PAI-1 deficient mice (B), there was comparatively greater TGF-β1 production but no evidence of intimal expansion and SMC migration.FootnotesCorrespondence to Douglas Vaughan, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn. E-mail [email protected] References 1 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.CrossrefMedlineGoogle Scholar2 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb. 1993; 13: 1865–1873.CrossrefMedlineGoogle Scholar3 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EK. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb. 1993; 13: 1090–1100.CrossrefMedlineGoogle Scholar4 Eren M, Painter CA, Atkinson JB, Declerck PJ, Vaughan DE. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation. 2002; 106: 491–496.LinkGoogle Scholar5 Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE. Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation. 2001; 104: 839–844.CrossrefMedlineGoogle Scholar6 Kaikita K, Schoenhard JA, Painter CA, Ripley RT, Brown NJ, Fogo AB, Vaughan DE. Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition. J Mol Cell Cardiol. 2002; 34: 617–627.CrossrefMedlineGoogle Scholar7 Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol. 1998; 18: 1771–1779.CrossrefMedlineGoogle Scholar8 Katoh M, Egashira K, Mitsui T, Chishima S, Takeshita A, Narita H. Angiotensin-converting enzyme inhibitor prevents plasminogen activator inhibitor-1 expression in a rat model with cardiovascular remodeling induced by chronic inhibition of nitric oxide synthesis. J Mol Cell Cardiol. 2000; 32: 73–83.CrossrefMedlineGoogle Scholar9 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 1995; 95: 995–1001.CrossrefMedlineGoogle Scholar10 Keeton MR, Curriden SA, van Zonneveld AJ, Loskutoff DJ. Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta. J Biol Chem. 1991; 266: 23048–23052.CrossrefMedlineGoogle Scholar11 Hua X, Miller ZA, Benchabane H, Wrana JL, Lodish HF. Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta-induced transcription of the Smad7 gene. J Biol Chem. 2000; 275: 33205–33208.CrossrefMedlineGoogle Scholar12 Datta PK, Blake MC, Moses HL. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta-induced physical and functional interactions between smads and Sp1. J Biol Chem. 2000; 275: 40014–40019.CrossrefMedlineGoogle Scholar13 Dong G, Schulick AH, DeYoung MB, Dichek DA. Identification of a cis-acting sequence in the human plasminogen activator inhibitor type-1 gene that mediates transforming growth factor-beta1 responsiveness in endothelium in vivo. J Biol Chem. 1996; 271: 29969–29977.CrossrefMedlineGoogle Scholar14 Hua X, Liu X, Ansari DO, Lodish HF. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Devel. 1998; 12: 3084–3095.CrossrefMedlineGoogle Scholar15 Otsuka G, Agah R, Frutkin AD, Wight TN, Dichek DA. Transforming growth factor beta 1 induces neointima formation through plasminogen activator inhibitor-1-dependent pathways. Arterioscler Thromb Vasc Biol. 2006; 26: 737–743.LinkGoogle Scholar16 Krag S, Danielsen CC, Carmeliet P, Nyengaard J, Wogensen L. Plasminogen activator inhibitor-1 gene deficiency attenuates TGF-beta1-induced kidney disease. Kidney Int. 2005; 68: 2651–2666.CrossrefMedlineGoogle Scholar17 Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, Vitacolonna E, Capani F, Consoli A. Plasminogen activator inhibitor type 1 is increased in the arterial wall of Type II diabetic subjects. Arterioscler Thromb Vasc Biol. 2001; 21: 1378–1382.CrossrefMedlineGoogle Scholar18 Weisberg AD, Albornoz F, Griffin JP, Crandall DL, Elokdah H, Fogo AB, Vaughan DE, Brown NJ. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol. 2005; 25: 365–371.LinkGoogle Scholar19 Smith LH, Dixon JD, Stringham JR, Eren M, Elokdah H, Crandall DL, Washington K, Vaughan DE. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. 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