doi: 10.1161/01.RES.0000207919.83894.9d
© 2006 American Heart Association, Inc.
Editorials |
GDF15, a Cardioprotective TGF-ß Superfamily Protein
From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, UMDNJ, New Jersey Medical School, Newark.
Correspondence to Junichi Sadoshima, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, UMDNJ, New Jersey Medical School, 185 South Orange Avenue, MSB G-609, Newark, NJ 07103. E-mail sadoshju{at}umdnj.edu
See related articles, pages 342–350 and 351–360
Key Words: GDF15 • TGF-ß superfamily • Smad • MAPK • hypertrophy • heart failure
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Introduction |
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 Top Introduction Is the Smad-Dependent Pathway...PerspectivesReferences |
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The transforming growth factor-ß (TGF-ß) superfamily proteins, comprising more than 40 members (broadly divided into the TGF-ßs/activins/nodal family and the bone morphogenetic proteins [BMPs]/Müllerrian inhibiting substance/growth and differentiation factors [GDFs] family), were originally identified as molecules important for regulating development, differentiation, and tissue repair in various organs.1 TGF-ß1, a founding member of the TGF-ß superfamily, plays a key role in mediating cardiac hypertrophy2 and remodeling after myocardial infarction (MI) as an autocrine/paracrine factor.3 Increased TGF-ß1 expression is considered one of the few molecular markers that potentially discriminate between compensated and decompensated cardiac hypertrophy.3 Although TGF-ß1 may function protectively after MI by promoting scar formation, inhibiting neutrophil infiltration, and facilitating cardiomyogenic differentiation of adult hematopoietic stem cells,4 such beneficial effects last only briefly and sustained activation of TGF-ß1 causes structural remodeling, eventually leading to cardiac failure.5 Thus, TGF-ß1 is generally regarded as detrimental, inducing cardiac hypertrophy and failure in the adult heart.
Compared with the wealth of knowledge regarding the effects of TGF-ß1 on the heart, much less is known as to how other members of the TGF-ß superfamily affect cardiac hypertrophy and failure.6 In this issue of Circulation Research, two companion articles report the effect of growth and differentiation factor 15 (GDF15), a 12-kDa secreted protein (and a 25-kDa disulfide-linked dimer) belonging to the TGF-ß superfamily, on cardiac hypertrophy and apoptosis.7,8 GDF15 is highly expressed in the placenta and the prostate, but not normally in many other organs, including the heart.9,10 However, expression of GDF15 is induced rapidly by IL-1, TNF
, and TGF-ß in macrophages, thereby limiting macrophage activation and inflammation (Figure 1).9 In addition, p53, a tumor suppressor protein, induces expression of GDF15, which acts as a growth inhibitory molecule in tumor cells (Figure 1).10 Such growth inhibitory actions of GDF15 are unique compared with those of other targets of p53, such as p21/Waf-1, because GDF15 can act on neighboring cells as an "extracellular" messenger after being secreted. Kemph et al found that expression of GDF15 is induced rapidly in cardiomyocytes on ischemia/reperfusion (I/R) via the nitric oxide-peroxynitrite-dependent signaling pathway.8 GDF15 is also upregulated by other cardiovascular events triggering oxidative stress, including pressure overload, heart failure,7 and atherosclerosis11 (Figure 1).
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In the heart, Gdf15 gene targeted mice exhibited greater hypertrophy, which could also be attributable to exaggerated hyperplasia, with reduced left ventricular function in response to pressure-overload,7 and a greater MI and apoptosis after I/R.8 This is in striking contrast with Tgfb1 gene targeted mice, in which angiotensin II–induced hypertrophy is abrogated.2 Conversely, heart-specific GDF15-overexpressing mice are resistant to pressure overload-induced hypertrophy.7 These results are consistent with the notion that GDF15 is a protective molecule for the heart. This leads to the question as to why GDF15 exerts cardioprotective effects whereas TGF-ß1 does the opposite, despite the fact that both activate similar downstream signaling pathways, including the Smad (Small mother against decapentaplegic)-dependent signaling pathway.
TGF-ß family proteins bind to distinct type I and type II serine/threonine kinase receptors. The specificity of the intracellular signaling is mainly determined by type I receptors (ALK1 to ALK7). Intracellular signaling mechanisms induced by the TGF-ß superfamily are broadly divided into Smad-dependent and -independent pathways (Figure 2).12 Receptor-activated Smads, including Smad2/3 and Smad1/5/8, are phosphorylated by type I receptors and, after forming a heterotrimeric complex with the common mediator Smad, namely Smad4, they are translocated into the nucleus and modulate transcription. The molecules activated by the Smad-independent pathway include MAPKs, TAK-1, and PI3K/Akt, although the precise mechanisms by which TGF-ß receptors activate these molecules are not clearly understood.12
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Is the Smad-Dependent Pathway Good or Bad for the Heart? |
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TopIntroductionIs the Smad-Dependent Pathway...PerspectivesReferences |
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Because the Smad-dependent pathway, the canonical TGF-ß signaling mechanism, is activated under several pathological conditions in the heart,13 it was postulated that the Smad-dependent pathway mediates detrimental functions of TGF-ß1. However, recent studies showed that this hypothesis may not necessarily be true. Wang et al reported a surprising observation that cardiac-specific Smad4 knockout mice resulted in cardiac hypertrophy and heart failure.14 Because Smad4 is considered the common transcriptional mediator of the Smad-dependent pathway, the observation by Wang et al suggests that the Smad-dependent pathway rather inhibits cardiac hypertrophy, apoptosis, and fibrosis, thereby acting in a protective manner. Although this observation does not exclude the participation of active Smads in hypertrophy and failure, the disadvantage caused by the lack of Smad4 overwhelms the few, if any, advantages to abolishing active Smad signaling in the heart. Xu et al found that Smad2 and Smad3 are phosphorylated on GDF15 treatment in cultured cardiomyocytes.7 Furthermore, adenovirus-mediated Smad2 overexpression suppressed hypertrophic responses, mimicking the effect of GDF15 overexpression.7 Together with the finding that GDF15 and Smad2 failed to show additive effects,7 these results strongly suggest that Smad2/3 mediate antihypertrophic and other cardioprotective effects of GDF15. Masaki et al reported that Smad1 is activated by I/R, which in turn reduces the size of MI and the amount of apoptotic cell death through upregulation of Bcl-xL and ß-catenin.15 Moreover, the loss of Smad5 also results in increased apoptosis in cardiomyocytes.16 Taken together, the Smad-dependent pathway appears to play antihypertrophic and antiapoptotic roles, thereby mediating the protective effect of GDF15 while counteracting the detrimental aspect of TGF-ß1 in the heart.
Besides GDF15, BMP-2 seems to have an antiapoptotic effect through activation of Smad1.6 However, the protective effects for the heart in vivo caused by BMP-2 remain to be shown. Thus, to our knowledge, GDF15 is the first TGF-ß superfamily protein that plays a cardioprotective role in vivo in the adult heart. Because GDF15 activates Smad2 and Smad3,7 ALK-4/5/7 could be the candidate receptors for GDF15. Alternatively, judging from the similarity in the primary structure and Smads activation, GDF15 may be closer to the BMP subfamily than to the TGF-ß subfamily.1 Because BMP-2 activates ALK-2/3/6, which in turn phosphorylate Smad1/5, GDF15 may also activate one of these type I receptors and Smad1/Smad5 as well.
What, then, is the signaling mechanism mediating the detrimental effects of the TGF-ß family? Among the various signaling mechanisms activated by TGF-ß1, the role of TAK-1 in mediating pathologic hypertrophy seems best established. TAK-1 is rapidly activated by TGF-ß1, and overexpression of TAK-1 in the heart causes cardiac hypertrophy and failure.17 Alternatively, the Smad-dependent mechanism may cooperatively mediate pathological hypertrophy in the presence of TAK-1 activation.13 In any case, it is possible that the Smad-independent pathway may determine whether each member of the TGF-ß superfamily mediates protective or detrimental functions in the adult heart. Interestingly, both ERKs and Akt, protective molecules for the heart, are activated by GDF15. In this regard, it would be interesting to confirm that TAK-1/p38 MAPK signaling is not actually activated by GDF15 in cardiomyocytes.
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Perspectives |
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TopIntroductionIs the Smad-Dependent Pathway...PerspectivesReferences |
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In summary, the studies reported by Xu et al7 and Kemph et al8 indicate that GDF15 is a promising cardioprotective agent against heart failure and I/R. A cautionary note is that GDF15 induces apoptosis in some cancer cells.18 Thus, the function of GDF15 may depend on the availability of type I and II receptors and/or Smads and concomitant activation of Smad-independent signaling mechanisms. Identifying the receptor subtype, the underlying signaling mechanism, and further downstream targets of GDF15 should be useful for further elucidation of the cardioprotective mechanism in various pathological conditions. It is advisable that the long-term protective effects of GDF15 overexpression on cardiac function after MI should be confirmed using GDF15 overexpression mice. Recently, several diffusible molecules, whose expression is strongly upregulated by cardiac stresses, have been identified as powerful cardioprotective factors.19,20 Because multicellular organisms are known to acquire "stress resistance" through stress-induced upregulation of diffusible factors which not only protect the cells under stress but also alert surrounding cells to prepare for coming disasters, identifying such molecules through expression profile analyses will continue to be a fruitful approach for future drug discovery.
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Acknowledgments |
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We thank Dr Stephen F. Vatner and Daniela Zablocki for critical reading of the manuscript.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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Related Article:
Circ. Res. 2006 98: 342-350.
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