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GDF15, a Cardioprotective TGF-␤ Superfamily Protein
Tetsuro Ago, Junichi Sadoshima
he transforming growth factor-␤ (TGF-␤) superfamily
proteins, comprising more than 40 members (broadly
divided into the TGF-␤s/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-␤1, a founding member of the TGF-␤ superfamily, plays a key role in mediating cardiac hypertrophy2
and remodeling after myocardial infarction (MI) as an autocrine/paracrine factor.3 Increased TGF-␤1 expression is considered one of the few molecular markers that potentially
discriminate between compensated and decompensated cardiac hypertrophy.3 Although TGF-␤1 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-␤1
causes structural remodeling, eventually leading to cardiac
failure.5 Thus, TGF-␤1 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-␤1 on the heart, much less is known as to how
other members of the TGF-␤ 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-␤ 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-␤ 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
T
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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).
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-␤1 does the opposite, despite the fact that both activate
similar downstream signaling pathways, including the Smad
(Small mother against decapentaplegic)-dependent signaling
pathway.
TGF-␤ 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-␤ 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 Smadindependent pathway include MAPKs, TAK-1, and PI3K/
Akt, although the precise mechanisms by which TGF-␤
receptors activate these molecules are not clearly
understood.12
Is the Smad-Dependent Pathway Good or Bad
for the Heart?
Because the Smad-dependent pathway, the canonical TGF-␤
signaling mechanism, is activated under several pathological
conditions in the heart,13 it was postulated that the Smaddependent pathway mediates detrimental functions of TGF␤1. 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
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
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 [email protected]
(Circ Res. 2006;98:294-297.)
© 2006 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/01.RES.0000207919.83894.9d
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Ago and Sadoshima
TGF-␤ Signaling in the Adult Heart
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Figure 1. Known upstream stimulators and functions of GDF15
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
␤-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-␤1 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-␤
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-␤ 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-␤ family? Among the various
signaling mechanisms activated by TGF-␤1, the role of
TAK-1 in mediating pathologic hypertrophy seems best
established. TAK-1 is rapidly activated by TGF-␤1, 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-␤ 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.
Perspectives
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 Smadindependent signaling mechanisms. Identifying the receptor
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Circulation Research
February 17, 2006
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Figure 2. Intracellular signaling pathways of TGF-␤ superfamily members and their cardiac effects. Bold lines indicate putative GDF15activated pathways. Note that some Smads may mediate hypertrophy and apoptosis in the presence of additional signaling mechanisms and transcription factors.
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.
Acknowledgments
We thank Dr Stephen F. Vatner and Daniela Zablocki for critical
reading of the manuscript.
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KEY WORDS: GDF15 䡲 TGF-␤ superfamily
䡲 hypertrophy 䡲 heart failure
䡲
Smad
䡲
MAPK
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GDF15, a Cardioprotective TGF-β Superfamily Protein
Tetsuro Ago and Junichi Sadoshima
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Circ Res. 2006;98:294-297
doi: 10.1161/01.RES.0000207919.83894.9d
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