From the Molecular Cardiology Unit (W.R.M., M.D.S.), Departments of
Medicine (W.R.M., M.D.S.), Cell Biology (M.D.S.), and Molecular Physiology and
Biophysics (M.D.S.), and Houston Veterans Affairs Medical Center (W.R.M.),
Baylor College of Medicine, Houston, Tex.
Correspondence to Michael D. Schneider, MD, Molecular Cardiology Unit, Baylor College of Medicine, One Baylor Plaza, Room 506C, Houston, TX 77030. E-mail michaels{at}bcm.tmc.edu
The temporal link
between cardiac hypertrophy and progressive myocardial
failure has been recognized for some time, although mechanistic
connections have been elusive. More than 100 years ago, Sir William
Osler described three classic stages of cardiac
hypertrophy, which culminate in "broken
compensation."1 Much research in recent years
has focused on identifying specific hypertrophic stimuli and dissecting
the corresponding signaling pathways to elucidate the events
responsible for this maladaptive transition. The development and
widespread adoption of molecular techniques to modify the genome,
chiefly in small mammals, have fueled this search and have provided
investigators a means to test the physiological
consequences of single gene defects, engineered in vivo. Toward this
end, both gain- and loss-of-function mutations have been used in
efforts to understand the biochemical pathways and molecular mechanisms
underlying the transition from cardiac hypertrophy to
failure, at least in mice, culminating in a robust and still-growing
array of transgenic models with a cardiomyopathic
phenotype similar in many respects to the human disease
state.
In this issue of Circulation, Sakata et
al2 report the progressive decompensation of
cardiac function after experimental pressure overload in transgenic
mice that overexpress the GTP-binding protein,
G
The findings in this report raise several important questions for our
understanding of mechanisms mediating cardiac hypertrophy
and its transition to myocardial dysfunction. Are the detrimental
effects of G
Sakata and colleagues2 anticipated an increased
growth response to load in G
Cardiac hypertrophy and adverse effects on
ventricular function also can be elicited by directed
expression of other G proteins—Gs
The number of transgenic mouse models that develop a phenotype
resembling human cardiomyopathy, to differing
degrees, has expanded dramatically in recent years. The impetus to
create such models can arise from the need to test the functional
significance of molecules whose expression or activity is known to be
altered in diseased hearts,9 including myosin
heavy chain mutations that can cause familial hypertrophic
cardiomyopathy,11 or the need
to provide in vivo validation for conclusions drawn from studies of
cultured cells. Importantly, advances in "microphysiology" have
dramatically extended the diagnostic armamentarium that is
available for mice.12 In many cases, a role for
these proteins in mediating left ventricular dysfunction
has been strengthened by observations of genetically altered mice.
Despite this potential for substantial informative results, transgenic
models (like all models) are imperfect. Although the extent to which
single gene defects can emulate acquired forms of
cardiomyopathy is both useful and gratifying, such
models may diverge at some level from the
pathophysiological response to chronic
hemodynamic stress or to load superimposed on the
substrate of ischemia or prior infarction. Thus it will be
intriguing to learn to what extent each model can successfully mimic
the human counterpart with respect to components of clinical heart
failure such as humoral factors or ß-adrenergic desensitization.
A second inherent limitation of protein overexpression in the heart is
the genetic equivalent of "pharmacological versus
physiological" dosing in drug studies: what is
the exact relevance of a maneuver that expresses a protein many fold in
excess of the levels in normal or diseased myocardium or
involves mutational activation of the protein? This highlights the
concept that a protein may sufficient to induce the phenotype
of hypertrophy or failure but not be necessary for these in
conventional pathophysiological settings.
Nonetheless, transgenic models are a powerful tool that can satisfy one
key criterion of Koch's postulates for causality in disease.
Definitive proof that a molecule is necessary for cardiac
decompensation in vivo will often require the converse approach, gene
deletion, and is likely to benefit from the refinement of conditional
systems to inactivate genes selectively in
myocardium13 or at predetermined
times to obviate global effects, embryonic death, or both. As
illustrations, the occurrence of dilated
cardiomyopathy in mice deficient for the
cytoskeletal muscle LIM-family protein, MLP,14 or
lacking Mn-superoxide dismutase,15 raises a
significant possibility that defects in these proteins' expression or
function may contribute to human heart failure.
Perhaps the most important aspect of the present study is the
authors' integration of a genetically engineered animal with a
microsurgical intervention to study the interplay of genes and
pathophysiology in vivo. The present study reaffirms the link
between cardiac hypertrophy and failure and heralds a new
approach to the study of this disease. It is hoped that a clearer
understanding of the pathways involved in cardiac
hypertrophy and failure will emerge from this form of
cross-disciplinary analysis, providing unique insights into
human disorders and auspicious models with which to design and test
potential therapies.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorials
Success in Failure
Modeling Cardiac Decompensation in Transgenic Mice
Key Words: Editorials • hypertrophy • pressure
q, selectively in cardiac muscle.
Gq-coupled receptors mediate signaling by
-adrenergic agonists, angiotensin II, and endothelin,
among other molecules with trophic or functional effects on the
myocardium. Previous studies amply demonstrate the ability
of Gq-coupled receptors and
Gq itself to stimulate hypertrophy in
neonatal cardiac myocytes grown in cell culture3 ;
however, their respective role in vivo requires more direct
substantiation. Agonist binding to this family of receptors increases
the proportion of Gq that is active (GTP-bound),
activating phospholipase C and ultimately protein kinase C. A previous
report by these investigators, directing the -subunit of
Gq to the myocardium in transgenic
mice, established the presence of hypertrophy and
measurable contractile dysfunction in the line used for the present
study as well (Gq-25), but not overt
congestive heart failure in the time frame
reported4 ; by contrast, lines that express higher
levels of Gq led to cardiac decompensation and
early death. In their present study, these authors sought to
determine the effects of Gq on
ventricular adaptation to pressure overload by subjecting
their Gq-25 transgenic mice to transverse
aortic banding.2 At baseline,
Gq ventricular myocytes exhibited
contractile dysfunction (intrinsic to the myocytes, shown by decreased
+dl/dt and –dl/dt). Impaired mechanical performance was
accompanied by the reexpression of a panel of fetal genes,
characteristic of plasticity seen in the pressure-overloaded
ventricle.5 After banding, however, the
transgenic ventricles developed pulmonary congestion, with
eccentric hypertrophy and a depressed ejection fraction,
unlike the compensated, concentric hypertrophy provoked in
normal mice. Whereas nontransgenic mice developed the characteristic
myocardial pattern of fetal gene expression, gene expression in the
Gq mice did not change further after banding.
Thus the key conclusion of the present study is that a single gene,
Gq, can modify the susceptibility to failure
after a pathophysiological intervention. q overexpression unique to this G
protein or true for this signaling pathway more generally? Do distinct
programs for G protein–dependent hypertrophy exist, as
suggested by differences among transgenic phenotypes? Are
differences in phenotype, among particular transgenes,
reconcilable with merely technical differences such as the resulting
levels of protein expression achieved or with differences in the
respective downstream intermediaries? From a clinical perspective, when
can cardiac hypertrophy be considered truly compensatory,
if hypertrophy itself predisposes to failure? What
inferences into human disease, mechanisms for congestive heart failure,
and potential countermeasures are suggested from the analysis
of genetically engineered mice? This editorial will attempt, briefly,
to address these issues and provide insight into the current status of
the use of transgenic mice as a tool for exploring the pathophysiology
of congestive heart failure. q mice after
aortic banding: rather than augmentation of concentric
hypertrophy, they found that hemodynamic
stress caused eccentric hypertrophy and rapid progression
to heart failure when superimposed on the background of growth due to
the Gq transgene. From the fact that the net
effect of Gq plus aortic banding was a
maladaptive form of hypertrophy, with cardiac
decompensation, one might extrapolate a role for
Gq in the development of left
ventricular failure induced by hemodynamic
stress more generally. If true, this supposition would encourage a
focus on Gq and
Gq-dependent proteins as potential
targets for drug development. One limitation of the present report
is that there remains a margin of uncertainty whether decompensation in
Gq mice after banding is necessarily due to
the specific signaling cascade activated by this G protein or,
alternatively, is related to the effects of hemodynamic
load superimposed on myocytes that are already compromised. Other
transgenic mice, with lower intramyocardial levels of
Gq, had normal function before banding, did
not display a propensity for decompensation, and were indistinguishable
from nontransgenic animals. This suggests that a threshold of
expression must be exceeded to develop the phenotype. , the
mediator of ß-adrenergic signaling,6 and RAS, a
mediator for various polypeptide growth factors and other trophic
signals7 —but the susceptibility to failure after
imposition of a load is not yet known in these models. Neither
overexpression of a constitutively active
1B-adrenergic receptor8
(which signals through Gq) nor overexpression
of RAS7 was sufficient for overt heart failure despite
similar or greater degrees of cardiac hypertrophy than in
Gq mice. By contrast, marked impairment of
left ventricular fractional shortening resulted from
directed expression of protein kinase C ß2, a known target for
Gq, through activation of phospholipase
C.9 Differing outcomes also have been reported
for fibrosis: present in the case of the transgenes encoding
Gs, RAS, or protein kinase C
ß26 7 9 and absent when hypertrophy
was induced by Gq4 or the
activated
1B-receptor.8 These
distinctions lend credence to the notion that activation of specific
signaling molecules might plausibly result in selective hypertrophic
phenotypes, with differing degrees of dysfunction, fibrotic
replacement, and failure. However logical, this conclusion may be
premature, because phenotypic differences are obvious even between
mouse lines expressing different amounts of
Gq2 4 or echo-selected
sublines of RAS transgenic mice.10 Moreover, the
intrinsic function of isolated ventricular myocytes was not
analyzed in most studies, nor have other transgenics been
subjected to pressure overload, the trigger for heart failure here, so
a definitive comparison of other genes' consequences versus
Gq is not feasible. Thus despite the
theoretical attractiveness of mouse genetics for identifying selective
mediators of adaptive versus maladaptive hypertrophy, the
graded phenotypes of Gq mice,
depending on gene dosage, may indicate instead that
hypertrophy and failure might be better viewed as a falling
along a continuum (at least for this mode of signal transduction). One
inherent ambiguity, common to these studies both of RAS and
heterotrimeric G proteins, is the existence of multiple agonists that
might signal through the proteins: in the case of
Gq, forced expression might emulate the signal
of 1-adrenergic agonists, endothelin, or
angiotensin II. Thus such experiments attest to a
biological role for the transducer but do not distinguish which
upstream signal is involved. A second issue is the potential for subtle
or overt differences between forced expression of the transducer versus
signaling by the ligand itself.
q-overexpressing mice.
Circulation.. 1998;97:1488–1495.
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  P. H. Sugden Signaling in Myocardial Hypertrophy : Life After Calcineurin? Circ. Res., April 2, 1999; 84(6): 633 - 646. [Full Text] [PDF]
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 P. C. Simpson ß-Protein Kinase C and Hypertrophic Signaling in Human Heart Failure Circulation, January 26, 1999; 99(3): 334 - 337. [Full Text] [PDF]
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