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TGFβ, cardiac fibroblasts, and the fibrotic response

 
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Abstract

The cytokine transforming growth factor β (TGFβ) is a major contributor to fibrogenic responses both in vitro and in vivo. TGFβ possesses many functions; thus, broadly targeting TGFβ signaling as an anti-fibrotic approach is anticipated to be problematic. Recent experiments, however, have begun to elucidate the signaling pathways through which TGFβ activates a fibrotic program. This review critically evaluates the evidence supporting TGFβ as a pro-fibrotic cytokine, with special attention to cardiac fibrosis, and suggests several possible points for selective drug intervention to combat chronic fibrotic disease.

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1. Introduction

Normal tissue repair requires that new connective tissue be produced. To achieve this end, fibroblasts must proliferate and migrate into the wound, where they remodel the extracellular matrix (ECM) by producing, adhere to and contracting the ECM, culminating in wound closure. The specialized form of fibroblast that performs this function is the myofibroblast, so-called as this cell type expresses the pro-contractile protein α-smooth muscle actin (α-SMA). During normal tissue repair, the myofibroblasts disappear, probably due to apoptosis, and normal tissue function is restored. However, should the tissue repair program not be appropriately terminated, myofibroblasts persist in the lesion, resulting in scarring [1,2]. Excessive deposition of scar tissue can result in chronic fibrotic diseases, which can affect not only the skin but also internal organs such as the kidney, liver, lung, or heart, and can culminate in organ failure resulting in death. As one of the major groups of disease with no therapy and given the significant contribution of chronic fibrotic diseases to health care costs, identifying rational, selective targets for anti-fibrotic drug intervention is imperative.

The fundamental mechanism underlying the excessive scarring observed in fibrotic disease is largely unknown, but has been the subject of intense research especially over the last decade. Results from many different laboratories have identified several major cytokines which contribute to fibrotic responses, including in vascular tissue. Perhaps the most important of these cytokines is transforming growth factor-β (TGFβ), which is induced during normal tissue repair and TGFβ induces fibroblasts to produce and remodel extracellular matrix (ECM) [3,4]. As TGFβ has several major roles in physiology, including as a suppressant of the immune system and epithelial proliferation, it is largely assumed that, from clinical and pharmaceutical standpoints, a better strategy to combat pathological fibrotic disease, compared to broad targeting of general TGFβ signaling pathways, would be to identify possible intervention points within the TGFβ signaling cascade that would attack the ‘bad’ TGFβ signaling leading to fibrosis, but leave other ‘good’ TGFβ-mediated events unaltered [5–7].

Although the exact contribution of TGFβ ligand and dysregulated TGFβ signaling to the pathogenesis of persistent pathological fibrosis is largely unclear, recent efforts have led to an increased awareness of the complexity regarding TGFβ signaling pathways, both directly downstream of TGFβ and in concert with other cytokines. The objective of this review is to assess the data supporting the role of TGFβ as a pro-fibrotic cytokine in animal models and in cardiac fibrosis, and to suggest possible intervention points for anti-fibrotic drug intervention in treating fibrotic disease, including that of the heart.

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2 TGFβ signaling

The general process underlying TGFβ signaling in fibroblasts has been extensively reviewed elsewhere [7,8]. Briefly, the three TGFβ isoforms TGFβ1, TGFβ2 and TGFβ3 are produced as an inactive form (complexed with latent TGFβ binding protein, or LTBP) and are activated by proteolytic cleavage, for example by plasmin or thrombospondin-1 (tsp-1) [9,10]. Active TGFβ binds to a complex of TGFβ type I and TGFβ type II receptors, resulting in the.phosphorylation of the receptor-activated Smads (R-Smads), Smad2 and 3, by the TGFβ receptor I kinase. Activated Smad2/3 binds Smad4 and become localized into the nucleus where they can activate transcription. The Smad3/Smad4 pair binds promoters at the Smad consensus sequence, CAGAC [11], whereas the Smad2-containing complex requires a nuclear DNA-binding protein of the family Fast (Fast-1) to bind DNA [12]. In adult fibroblasts, Smad3 is essential for the activation of essentially all TGFβ responsive genes [13]. Smads themselves are weak transcriptional activators, and act with general transcriptional cofactors such as p300, and specific basal transcription factors, which vary depending on the promoter of interest, to form an active transcriptional complex on promoters [7]. Inhibitory Smads Smad6 or Smad7, can prevent R-Smad activation, by competing for binding for Smad2 and Smad3 to the TGFβR1 and by enhancing receptor degradation [13,14]. TGFβ can suppress its own action via the transcriptional induction of Smad7 [15; Fig. 1].

Fig. 1
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Fig. 1

TGFβ signaling generally occurs through TGFβ type I and type II receptors and Smads, and also acts through ancillary proteins. TGFβ binds to the TGFβ type I and type II receptors. The type I receptor contains kinase activity, and phosphorylates receptor-activated Smads, Smad2 and 3, which dimerize with Smad4. The resultant complex migrates into the nucleus to activate target gene expression. TGFβ induces the inhibitory Smads, Smad6 and 7, which block TGFβ receptor type I-dependent Smad 2/3 activation. Syndecan 4 mediates the TGFβ-induction of ERK [40]. In cardiac fibroblasts, angiotensin II (Ang II) also induces the TGFβ ancillary receptor endoglin [26], which may modulate the pro-fibrotic effects of TGFβ in this cell type, although endoglin suppresses the Smad3 pathway in fibroblasts [27].

Increasingly it is appreciated that TGFβ also causes the activation of other signaling pathways, such as the MAP kinase or focal adhesion kinase cascades which appear to act, in a promoter-dependent fashion, to activate transcription [16–19]. As a specific example, blocking the ras/MEK/ERK pathway does not significantly affect the induction of a promoter containing only multiple Smad3-binding elements, but attenuates the Smad3-dependent TGFβ-mediated induction of connective tissue growth factor (CTGF,CCN2) protein production and promoter activity [16–18]. Thus, whereas transcriptional responses to TGFβ generally require the type I and type II TGFβ receptors and the Smads, the specificity of transcriptional responses to TGFβ relies on: (a) the ancillary signaling pathways induced by TGFβ and (b) the basal transcription factors acting with Smads (Fig. 1).

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3 TGFβ as a downstream mediator of angiotensin

TGFβ is at a key central position in mediating fibrogenic responses (Fig. 2). It has long been appreciated that angiotensin II (Ang II) is an important driving force in fibrogenesis including in the heart [19], and it is now appreciated that TGFβ is an essential downstream mediator of the pro-fibrotic effects of Ang II. Ang II upregulates TGFβ1 in cardiac fibroblasts [20,21]. Ang II antagonists block the increased expression of TGFβ1 in cardiac and vascular tissue in rats [22]. In human atrial myocardial tissue, Ang II indirectly induces collagen expression, through upregulating TGFβ1 [23]. The ability of Ang II to induce TGFβ activity appears to be mediated at least in part by ability of Ang II to induce tsp-1, as peptide antagonists of tsp-1-mediated TGFβ activation blocked Ang II and glucose-induced TGFβ activation in cardiac fibroblasts [24]. Furthermore, Ang II-induced heart failure involves Smads, suggesting that TGFβ is involved in this process [25]. Intriguingly, Ang II may promote the pro-fibrotic effects of TGFβ by inducing expression of the TGFβ ancillary receptor endoglin, although the mechanism underlying endoglin action is unclear [26; Fig. 1]. However, as overexpression of endoglin in normal fibroblasts results in the suppression of Smad3-dependent signaling [27], the role of endoglin may actually be anti-fibrotic.

Fig. 2
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Fig. 2

Schematic diagram of interplay among pro-fibrotic cytokines. Angiotensin II (Ang II) induces TGFβ, CTGF and ET-1 directly; TGFβ induces ET-1 and CTGF; ET-1 induces CTGF (for details see text).

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4 Direct evidence for TGFβ as a pro-fibrotic cytokine

Evidence supporting the contribution of TGFβ itself in driving fibrotic responses has been derived mainly using acute in vitro or in vivo models. For example, treatment of fetal wounds with TGFβ promotes wound closure and scarring [28]. In addition, injection of TGFβ, either directly subcutaneously or into metal chambers, results in enhanced deposition of ECM [28,29]. Furthermore, incisional rat wounds treated with anti-TGFβ antibodies or anti-sense oligonucleotides show a marked reduction in ECM synthesis and scarring [30,31]. Both TGFβ 1 mRNA abundance and protein levels are significantly increased in cardiac infarct scar, correlating with increased collagen type I expression and elevated Smads 2, 3, and 4 [32], but reduced Smad7 [33], expression suggesting that heightened responses to TGFβ may significantly contribute to cardiac fibrosis. TGFβ directly induces collagen production and ECM contraction by fibroblasts, including those isolated from heart tissue [34]. Overexpression of TGFβ in heart, under the control of the albumin promoter, causes myocardial fibrosis [35]. TGFβ1, β3 and LTBP are increased in patients with cardiac fibrosis associated with valve replacement surgery, suggesting an involvement of active TGFβ in cardiac fibrogenesis [36].TGFβ1 deficient mice display markedly reduced collagen deposition compared to control mice, such mice also show a severe wasting syndrome accompanied by a pronounced, generalized inflammatory response and tissue necrosis, resulting in organ failure and death [37,38]. These results are consistent with the fact that, as discussed above, TGFβ is pleiotropic and that broad targeting of TGFβ in humans is likely to have adverse side-effects [5,7]. Consistent with the notion that blocking TGFβ action may be problematic clinically, TGFβ type I receptor inhibition inhibits the overexpression of type I collagen and the enhanced ECM contraction by fibrotic dermal fibroblasts isolated from scars of scleroderma patients, but also significantly affects basal type I collagen production and ECM contraction by normal fibroblasts [39,40]. Furthermore, addition of TGFβ ligand to cells or mice causes only a transient fibrotic response, which persists only as long as TGFβ ligand is present [29]. However, TGFβ can promote persistent fibrotic responses in vivo, but only in the presence of cofactors, such as connective tissue growth factor (CTGF,CCN2) [29]. These issues point to the potential difficulty of broadly targeting the TGFβ axis in developing anti-fibrotic therapies, and indicate that specific intervention points downstream of TGFβ ligand and receptors are required. It should be pointed out, however, confirmation of the suitability of approaches employing neutralizing TGFβ antibodies and receptor antagonists awaits proper evaluation in animal models of fibrosis and, ultimately, possibly in humans.

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5 Gene-specific pathways contributing to fibrogenesis

It is likely, then, that targeting the ability of TGFβ to induce gene-specific pathways will be of benefit in generating selective therapies for fibrotic disease. In dermal fibroblasts and mesangial cells, TGFβ transiently activates the ras/MEK/ERK cascade, which is required for the induction of CTGF expression [16–18], actin stress fiber formation and ECM contraction [40,41]. Intriguingly, in both mesangial cells and fibroblasts, TGFβ induction of a generic Smad3-responsive promoter occurs in the presence of either dominant negative ras or the MAP kinase inhibitor U0126, indicating that the absolute requirement for the ras/MEK/ERK cascade in the induction of TGFβ-responsive genes seems to be restricted in a promoter-specific fashion [16–18]. The stable prostacyclin analog Iloprost, which alleviates symptoms of fibrosis in vivo and reduces CTGF expression and TGFβ-induced collagen deposition, acts at least in part by antagonizing the ras/MEK/ERK cascade via the elevation of cAMP [18]. In a rat model of cardiac fibrosis, the ERK pathway, in addition to the Smads, is activated and may contribute to Ang II-induced fibrosis in this model [25]. Thus understanding how TGFβ activates ERK is likely beneficial in identifying targets for drug intervention in fibrosis. In dermal fibroblasts, the ability of TGFβ to induce ERK is prevented in the absence of the proteoglycan syndecan 4 [40; Fig. 1]. Syndecan 4 knockout mice appear normal, but show a reduced tissue repair response demonstrating the selectivity of syndecan 4 action [42], and suggest that targeting syndecan 4 might be a useful anti-fibrotic approach. Similar mechanisms may also operate in cardiac fibroblasts.

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6 Synergy between TGFβ and other cytokines.

As mentioned above, TGFβ itself is insufficient to result in persistent fibrotic responses in vivo or in vitro, and that synergy between TGFβ and other extracellular ligands such as CTGF and endothelin-1 (ET-1) is required.

6.1 CTGF

CTGF, a member of the CCN family of proteins [43,44], is not normally expressed in adult mesenchymal cells, but is induced during tissue repair and characteristically overexpressed in fibrotic disease, including cardiac fibrosis, in a fashion correlating with severity of fibrosis [45,46]. CTGF expression is induced by TGFβ through Smads, Ets-1, protein kinase C and ras/MEK/ERK [16–18,47,48]. Ang II also induces CTGF in cardiac fibroblasts, through a protein kinase C-dependent mechanism, although it is unclear as to whether TGFβ acts as an intermediary in this process or if AngII induces CTGF directly [49]. Although CTGF itself causes only modest fibrotic responses, CTGF and TGFβ act together to promote sustained fibrosis in rodents [29]. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFβ expression are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFβ during pathological fibrotic responses in the heart [50]. CTGFdeficient embryonic fibroblasts show an intact response to TGFβ through the Smad pathway, yet show an impaired induction of TGFβ-induced adhesive signaling, and a concomitant inability to induce a variety of pro-fibrotic mRNAs and proteins including α-SMA and type I collagen [51]. Furthermore, siRNA targeting CTGF expression has recently been shown to block carbon tetrachloride-induced liver fibrosis, including collagen expression [52]. These results suggest that targeting CTGF expression might be of benefit in selectively targeting fibrotic responses [53].

6.2 ET-1

When added to fibroblasts, the endothelial cell produces endothelin-1 (ET-1) induces a program of ECM synthesis and contraction [54,55], and can act synergistically with TGFβ [56,57]. Blockade of the endothelin receptors with a dual endothelin receptor A and B (ETA/B) antagonist significantly reduces α-SMA overexpression and ECM contraction by fibrotic lung fibroblasts [54]. Significantly, and in contrast to TGFβ receptor antagonism [39,40], ETA/B receptor blockade does not block basal fibroblast activity [54]. The ETA/B receptor antagonist bosentan is currently used clinically to treat pulmonary hypertension and the formation of new digital ulcers in scleroderma patients [58,59]. ET-1 is a powerful vasoconstrictor and has been associated with conditions including systemic and pulmonary hypertension, congestive heart failure, vascular remodeling renal failure, cancer, and cerebrovascular disease. ET-1 acts as a potent growth factor, including on cardiac fibroblasts [60]. ET-1 concentrations correlate with measures of ventricular remodeling in patients with ischemic heart failure and dilated cardiomyopathy [61] and in rats with coronary artery ligation-induced heart failure [62]. It has been recently demonstrated that cardiac overexpression of ET-1 could be related to increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death [63]. TGFβ induces ET-1 in fibroblasts through a JNK-dependent Smad-independent mechanism [64]. That ET-1 is a downstream mediator of the pro-fibrotic action of TGFβ is illustrated by the observation that bosentan blocks the ability of TGFβ to induce the expression of the key pro-fibrotic marker and mediator α-SMA by pulmonary fibroblasts isolated from scars of scleroderma patients [64]. Furthermore, it has recently been shown that Ang II can also induce ET-1 in cardiac fibroblasts [65]. ET-1 can in turn induce CTGF expression [55] suggesting that Ang II, TGFβ and ET-1 act together to promote fibrogenesis, and possibly that ET-1 or CTGF may be a common downstream mediator of Ang II or TGFβ-induced fibrosis (Fig. 2). ETA/B receptor antagonism is well tolerated in patients, but it remains unclear whether such therapy is effective in suppressing fibrosis in patients.

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7 Conclusion

The potent pro-fibrotic cytokine TGFβ induces matrix synthesis in fibroblasts and fibrotic responses in vivo and in vitro. Genetic and pharmacological studies have suggested that broad targeting of general TGFβ signaling pathways might be problematic for treating fibrotic disease due to the pleiotropic nature of TGFβ. The past several years has led to an appreciation that additional pathways and receptors to the generic, universal TGFβ/TGFβ type I and type II receptor/Smad axis contribute to TGFβ-induced fibrotic responses. These include syndecan 4, ras/MEK/ERK, CTGF and ET-1. By manipulating these ancillary pathways, selective anti-fibrotic effects might be achieved and lead to the development of appropriate therapies for fibrotic disease.

  1. Andrew Leask*
  1. CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London ON, Canada N6A 5C1
  1. *Tel.: +1 519 661 2111x81102. Email address: Andrew.Leask{at}schulich.uwo.ca
  • Received June 1, 2006.
  • Revision received July 7, 2006.
  • Accepted July 11, 2006.
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Acknowledgements

AL is supported by the Canadian Institute of Health Research and the Canadian Foundation for Innovation and an Arthritis Society (Scleroderma Society of Ontario) New Investigator.

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Footnotes

  • Time for primary review 32 days

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  1. Cardiovasc Res (2007) 74 (2): 207-212. doi: 10.1016/j.cardiores.2006.07.012
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