NEWS & VIEWS

Sensing heart stress

Heart failure and pathological overgrowth of the heart often occur hand in hand. New data on a biomechanical
sensor challenge the viewpoint that cardiac hypertrophy causes heart failure (pages 6875).

T he main function of the heart is to

provide adequate delivery of oxygen
to meet the metabolic demands of the
LIZA BARKI-HARRINGTON &
HOWARD A. ROCKMAN
ligands in the ECM (for example, colla-
gen, fibronectin and laminin) initiates
signaling in multiple intracellular path-
body under conditions of normal and ways through integrin-bound proteins
2003 Nature Publishing Group http://www.nature.com/naturemedicine

increased workload. Although the per- tracellularly and result in altered gene that regulate gene expression, cell growth
formance of the heart is well maintained expression and protein synthesis that and survival4,5. One of the candidate pro-
over a wide range of physiological stres- lead to an enlarged heart. teins to act as a biomechanical sensor in
sors, increased biomechanical stress Although many of the factors that ini- this pathway is melusin, which interacts
from either exercise or disease can drive tiate GPCR-mediated hypertrophy have with the cytosolic domain of integrin
morphological changes in the heart been studied extensively, the role of bio- and is expressed exclusively in skeletal
muscle, known as cardiac and cardiac muscle5.
hypertrophy. Cardiac hy- In this new report1, the
pertrophy is an increase Pressure overload authors examined the
in mass of the heart due role of melusin in the de-
primarily to an increase in velopment of cardiac hy-
cell size, which under cer- pertrophy in response to
tain conditions progresses GPCRs Integrins two different models.
RTKs
into heart failure. The Cytokines Mice that are genetically
molecular and cellular deficient for the melusin
mechanisms that are at gene were exposed to ei-
Gq
the base of the pathologi- ther biomechanical stress
cal transition from cardiac through physical con-
hypertrophy to cardiac Melusin
striction of the aorta7, or
failure have been the sub- hormonally induced car-
ject of intense investiga- Hypertrophy diac hypertrophy through
tion for over a half activation of Gq-coupled
century. In this issue, receptors at doses that do
Brancaccio et al.1 address not induce elevation in
the fundamental question blood pressure. The most
of how biomechanical important finding of this
stress translates into bio- study is that melusin was
chemical changes inside a critical only for the devel-
Kimberly Homer

heart muscle cell. They opment of biomechani-

show that the integrin- cally induced cardiac
Heart failure No heart failure
bound protein melusin hypertrophy, whereas it
acts as a biomechanical Fig. 1 Signaling pathways in the development of cardiac hypertrophy in re- was not involved in hor-
sensor, and that it is pro- sponse to pressure overload. Pressure overload initiates signaling in multiple monally induced hyper-
tective against the adverse pathways that result in cardiac hypertrophy. Melusin is a biomechanical trans- trophy or in normal heart
effects of pressure over- ducer that is selectively involved in integrin-mediated hypertrophy, and is pro- function and develop-
load. tective against the development of heart failure. In contrast, activation of other ment. Moreover, mice that
Pressure-overloadin- signaling pathways that also lead to cardiac hypertrophy, such as Gq-coupled re- were melusin-deficient de-
ceptors, is deleterious and often progresses to heart failure. Progression to heart
duced cardiac hypertro- veloped heart failure in re-
failure is unlikely to be related to the development of hypertrophy, but rather is
phy, such as that caused likely to be related to the intricate balance between the activation of protective sponse to biomechanical
by chronic hypertension, and deleterious signaling pathways. pressure overload. The au-
is triggered by two major thors further identified a
types of input that result role for melusin in the ac-
in an enlarged muscle: (1) mechanical mechanical sensor molecules in cardiac tivation of a specific signaling pathway
stress and (2) neural and humoral fac- hypertrophy is less understood. involved in mediating the hypertrophic
tors that activate growth factor receptor Transduction of mechanical stress into response. Together their data indicate
tyrosine kinases (RTKs), cytokine recep- biochemical signals is largely mediated that the actions of melusin are restricted
tors and G-protein-coupled receptors2 by a group of cell surface receptors called to integrin-mediated signaling pathways
(GPCRs), particularly those that couple integrins, which link the extracellular activated by mechanically induced pres-
to the Gq class of heterotrimeric gua- matrix (ECM) to the cellular cytoskele- sure overload.
nine-nucleotide binding regulatory pro- ton, thus providing physical integration A long-standing controversy has cen-
teins (G proteins)3. Signals originating between the outside and the inside of the tered on whether the development of
from all of these pathways converge in- cell. Activation of integrins by different cardiac hypertrophy is protective

NATURE MEDICINE VOLUME 9 NUMBER 1 JANUARY 2003 19

 NEWS & VIEWS
against the deterioration into heart fail-
ure. The long-held view has been that
cardiac hypertrophy in response to
pathological overload serves to restore
heart muscle stress back to normal and
counteracts the progressive deteriora-
tion of cardiac function. However, re-
cent studies have demonstrated that
cardiac hypertrophy is not critical for
the prevention of cardiac deterioration.
2003 Nature Publishing Group http://www.nature.com/naturemedicine
Rather it is the chronic activation of
Gq-coupled receptors and other signal-
ing pathways that is harmful8,9. Given
the observation that the lack of
melusin prevents the development of
cardiac hypertrophy and promotes
heart failure, Brancaccio et al. deduce
that hypertrophy prevents the deterio-
ration in cardiac function. While their
data are certainly intriguing, we offer a
different interpretation of it. In our
opinion, progression to cardiac failure
does not depend on the phenotype of
hypertrophy, but rather is related to the
intricate balance between the activa-
tion of protective and deleterious sig-
naling pathways. In this regard, the
novel contribution of Brancaccio et al.
lies in the identification of a molecule
that is involved in a hypertrophic sig-
naling pathway and is also protective
Setting the cytokine trap for autoimmunity
Agents that block the action of specific cytokines have changed the lives of many patients with rheumatoid arthritis
and other autoimmune disorders. But frequent self-injections or injections by a physician during a clinic visit are
required. Now a new class of anti-cytokine that may bypass such problems appears on the horizon (pages 4752).
P rotein-based agents that block the ac-
tion of cytokines have substantially im-
proved treatment for patients with
autoimmune diseases over the last five
years. Diseases such as rheumatoid arthri-
tis, psoriasis and Crohns inflammatory
bowel disease are now routinely treated
with agents such as neutralizing mono-
clonal antibodies to tumor necrosis factor
(TNF; Remicade, also known as inflix-
imab). Other agents include receptors to
TNF (Enbrel or etanercept) and the inter-
leukin-1 receptor antagonist (IL-1Ra;
Kineret or anakinra). These specific anti-
cytokinebased therapies can reduce in-
flammation and joint destruction in
rheumatoid arthritis, are being used in
over 250,000 patients and have validated
the importance of IL-1 and TNF in inflam-
matory diseases. But the current repertoire
of agents has some drawbackschief
among them is the relatively short half-
life, which necessitates frequent injections
20
against the development of heart fail-
ure. In contrast, the activation of Gq-
coupled receptor signaling pathways,
which also culminates in the same phe-
notype of cardiac hypertrophy, is dele-
terious and often progresses to cardiac
enlargement and heart failure9,10. It is
not the hypertrophy per se that deter-
mines a detrimental outcome, but
rather the different signaling pathways
that are activated in response to the
chronic overload state of the heart.
Indeed, a recent study supports the
finding of a protective role for integrins
against the development of pressure-
overloadinduced heart failure4.
The identification of the precise inter-
section between the integrinmelusin
pathway and other signaling pathways
will be of great importance in under-
standing the complexity of the hyper-
trophic response that leads to heart
failure. Further investigation will likely
provide the exact molecular mecha-
nisms involved in pressure-overloadin-
duced cardiac hypertrophy and perhaps
lead to novel therapeutic opportunities
for the treatment of this deadly disease.
1. Brancaccio, M. et al. Melusin, a muscle-specific in-
tegrin 1-interacting protein, is required to pre-
vent cardiac failure in response to chronic
CHARLES A. DINARELLO
or intravenous infusions. Fully human
agents with high affinities and long bio-
logical half-lives would provide improved
therapeutic options.
To that end, Economides et al. have de-
veloped novel cytokine traps1 which take
advantage of the way that cytokines bind
to the extracellular domains of their cell
surface receptors. In general, cytokines
such as IL-1, IL-4 or IL-18 first bind to a
single surface receptor protein chain with
a relatively low affinity. But this binding
does not result in signal transduction; in-
stead, binding results in recruitment of a
second, usually structurally distinct pro-
tein chain. It is this new complex of the
cytokine bound to the two receptor chains
that initiates the signal (Fig. 1). The cy-
tokine binds to the two-chain complex
considerably more tightly than that to the
NATURE MEDICINE VOLUME 9 NUMBER 1 JANUARY 2003
pressure overload. Nature Med. 9, 6875 (2003).
2. Molkentin, J.D. & Dorn, I.G., 2nd. Cytoplasmic
signaling pathways that regulate cardiac hyper-
trophy. Annu. Rev. Physiol. 63, 391426 (2001).
3. Akhter, S.A. et al. Targeting the receptor-Gq in-
terface to inhibit in vivo pressure overload my-
ocardial hypertrophy. Science 280, 574577
(1998).
4. Shai, S.Y. et al. Cardiac myocyte-specific excision
of the 1 integrin gene results in myocardial fi-
brosis and cardiac failure. Circ. Res. 90, 458464
(2002).
5. Giancotti, F.G. & Ruoslahti, E. Integrin signaling.
Science 285, 10281032 (1999).
6. Brancaccio, M. et al. Melusin is a new muscle-spe-
cific interactor for (1) integrin cytoplasmic do-
main. J. Biol. Chem. 274, 2928229288 (1999).
7. Rockman, H.A. et al. Segregation of atrial-specific
and inducible expression of an atrial natriuretic
factor transgene in an in vivo murine model of
cardiac hypertrophy. Proc. Natl. Acad. Sci. USA
88, 82778281 (1991).
8. Rockman, H.A., Koch, W.J. & Lefkowitz, R.J.
Seven-transmembrane-spanning receptors and
heart function. Nature 415, 206212 (2002).
9. Esposito, G. et al. Genetic alterations that inhibit
in vivo pressure-overload hypertrophy prevent
cardiac dysfunction despite increased wall stress.
Circulation 105, 8592 (2002).
10. Adams, J.W. et al. Enhanced Gq signaling: A
common pathway mediates cardiac hypertrophy
and apoptotic heart failure. Proc. Natl. Acad. Sci.
USA 95, 1014010145 (1998).
Department of Medicine, Cell Biology,
and Genetics
Duke University Medical Center
Durham, North Carolina, USA
Email: h.rockman@duke.edu
first protein chain due to two distinct
binding domains on the cytokine, which
each bind to the separate chains2. The nat-
urally occurring IL-1Ra lacks the second
binding domain and does not recruit the
second chain in the receptor complex.
The cytokine trap takes advantage of the
two separate receptor chains, which to-
gether provide high-affinity binding. The
cytokine trap provides both receptor
chains in a dimeric configuration that re-
sembles the two chains of extracellular cell
surface receptor. The trap is, however, dif-
ferent in that each arm of the dimeric
structure is identical and contains do-
mains of both receptor chains. The two
chains of the trap are linked by fusion of
the complement binding domain of IgG1.
As such, the structure is not natural, but is
composed of solely natural proteins. The
structures are stable, bind cytokines with
high affinity and have the potential to
supplant current therapies.