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Review Articles

Mechanisms of Disease

FRANKLI N H. E

P STEI N

, M.D.,

Editor

1276

October 21, 1999

The New England Journal of Medicine

S

IGNALING

P

ATHWAYS

FOR

C

ARDIAC

H

YPERTROPHY

AND

F

AILURE

J

OHN

J. H

UNTER

, M.D.,

AND

K

ENNETH

R. C

HIEN

, M.D., P

H

.D.

From the University of California San DiegoSalk Institute Program inMolecular Medicine, Department of Medicine and Center for MolecularGenetics, University of California San Diego School of Medicine, La Jolla,Calif. Address reprint requests to Dr. Chien at the Department of Medi-cine, 0613-C, University of California San Diego, 9500 Gilman Dr., LaJolla, CA 92093, or at [email protected].

1999, Massachusetts Medical Society.

EART failure is a leading cause of mortalityin the United States. As a result of advancesin genetic technology, a molecular basis of

heart failure is emerging.

1,2

This review highlights theways in which these insights are leading to new ther-apeutic targets in patients with acquired forms ofheart failure.

MORPHOLOGIC CLASSIFICATION

OF CARDIAC HYPERTROPHY

Myocardial hypertrophy is an early milestone dur-ing the clinical course of heart failure and an impor-tant risk factor for subsequent cardiac morbidity andmortality. In response to a variety of mechanical, he-modynamic, hormonal, and pathologic stimuli, theheart adapts to increased demands for cardiac workby increasing muscle mass through the initiation ofa hypertrophic response. At the cellular level, cardiacmyocytes respond to biomechanical stress by initiat-ing several different processes that lead to hypertro-phy (Fig. 1). The so-called physiologic hypertrophythat occurs in elite athletes is associated with pro-portional increases in the length and width of car-diac myocytes. By contrast, the assembly of contrac-tile-protein units in series characterizes the eccentrichypertrophy that occurs in patients with dilated car-diomyopathy, with a relatively greater increase in thelength than in the width of myocytes. During pres-

sure overload, new contractile-protein units are as-sembled in parallel, resulting in a relative increase in

H

the width of individual cardiac myocytes and there-

fore in concentric hypertrophy. In hypertrophic car-diomyopathy, mutant contractile proteins lead tomyofibrillar disarray and secondary hypertrophy ofmyocytes. In most forms of cardiac hypertrophy, thereis an increase in the expression of embryonic genes,including the genes for natriuretic peptides and fetalcontractile proteins.

3

The induction of the natriuret-ic peptide genes is a feature of hypertrophy in allmammalian species and is a prognostic indicator ofclinical severity. Recently, evidence of the loss of my-ocytes as a result of programmed cell death (apop-tosis) has also been reported in both experimentaland clinical cardiac hypertrophy (Fig. 1).

GENETIC METHODS OF STUDYINGCARDIAC HYPERTROPHY AND FAILURE

Cardiac hypertrophy and failure are highly complexdisorders that arise as a result of a combination ofgenetic, physiologic, and environmental factors. Theidentification of mutations involving a single genethat are responsible for inherited forms of hyper-trophic cardiomyopathy, dilated cardiomyopathy, and

ventricular arrhythmogenesis (the long-QT syndrome)has allowed us to pinpoint several of the initiatingevents that can lead to features of heart failure in hu-mans.

4,5

There is still a broad gap, however, betweenidentifying the defective gene and understanding howthis defect leads to the cardiac abnormalities. In thisregard, in vitro assays of cardiac muscle cells and stud-ies of genetically engineered animals are beginningto identify the points in cardiac growth signaling thatcause these distinct forms of cardiac hypertrophy andfailure.

Assays of Cardiac-Muscle Cells

The ability to culture primary cardiac myocyteshas resulted in the availability of a well-characterizedin vitro system in which to study the hypertrophicresponse. Although they are based on neonatal car-diac-muscle cells, studies of these cultures have ledto the identification of signaling pathways that acti-

vate cellular responses known to occur during hy-pertrophy in vivo, including an increase in cell size,an increase in the expression of embryonic genes, andthe accumulation and assembly of contractile pro-teins.

6

By altering the expression of specific genes incultured cardiac myocytes, peptide hormones, growthfactors, and cytokines have been identified that canactivate specific features of the hypertrophic response(Table 1).

7

Among the most extensively characterizedof these substances are endothelin and angiotensinII, insulin-like growth factor I, and other growth

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MECHANISMS OF DISEASE

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Figure 1.

Morphology of Ventricular Muscle Cells in Cardiac Hypertrophy and Failure.

Phenotypically distinct changes in the morphology of myocytes occur in response to various growth stimuli. The expression ofembryonic genes such as natriuretic peptides is increased in both eccentric and concentric hypertrophy, but not in physiologic hy-

pertrophy, in response to exercise. Myofibrillar disarray (sarcomeric disorganization) is typical of hypertrophic cardiomyopathies;this disorganization is focal and is accompanied by more widespread increases in the cross-sectional area of myocytes.

*A more complete description of each of these classes has been published.

7

T

ABLE

1.

P

OTENTIAL

T

HERAPEUTIC

AND

M

OLECULAR

T

ARGETS

IN

THE

S

IGNALING

P

ATHWAYS

I

NVOLVED

IN

H

EART

F

AILURE

.*

G

OAL

T

YPE

OF

D

RUGS

M

OLECULAR

T

ARGET

Inhibition of pathologic hyper-trophy

Antagonists of G

q

a

-dependent receptors Angiotensin II receptorEndothelin-1 receptor? Novel receptors

Inhibitors of intracellular kinasecascades

Antagonists of ras, p38, and c-junN-terminal kinase (JNK)

? Novel kinasesPromotion of physiologic hyper-

trophyGrowth hormoneInsulin-like growth factor I

Growth-hormone receptorInsulin-like growth factor I receptor

Inhibition of neurohumoral over-stimulation

Beta-blockers

b

1

-Adrenergic receptor

Enhancement of contractile andrelaxation responses

Relief of inhibition of sarcoplasmic retic-ulum calcium ATPase

Agents that counteract the desensitiza-tion of G proteincoupled receptorkinases

Phospholamban inhibitors

Inhibitors ofb

-adrenergicreceptor kinase

Relief of energy depr ivation Angiogenic growth factors Vascular endothelial-der ived growth factorFibroblast growth factor 5

Agents involved in angiogenesis? Others

Inhibition of pathways of apopto-sis of myocytes

Promoters of myocyte survival gp130 ligands (e.g., cardiotrophin 1)Neuregulin

Inhibitors of apoptosis Caspase inhibitorsInhibitors of cytokines Tumor necrosis factor a

, ? others

Growth

stimuli

Apoptosis Physiologic hypertrophy

Concentric hypertrophy

Eccentric hypertrophy

Increased expression

of embryonic genes

Sarcomeric disorganization

Normal muscle cell



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factors that activate either heteromeric (G

q

) or low-molecular-weight guanosine triphosphate (GTP)binding protein (ras) signaling pathways, as well ascardiotrophin 1 and other members of the interleu-kin-6 cytokine family that activate cellular responsesby means of the transmembrane signal transducergp130. A relatively distinct pattern of cardiac cellularresponses has been associated with each of thesesubstances, implying that their actions are specific.To a certain extent, this specificity reflects the acti-

vation of different downstream intracellular kinasecascades that stimulate the appearance of specific fea-tures of myocardial-cell hypertrophy (Fig. 2). Studyof these downstream signaling pathways has identi-fied kinases that generate primarily hypertrophic, ap-optotic, and anti-apoptotic signals,

8-10

as well as ki-nases that regulate the assembly of myofilaments (rhokinase).

11

In addition, nuclear signaling proteins havebeen found that activate and suppress various cardiacgenes during hypertrophy.

7

Cardiac Hypertrophy and Failurein Genetically Altered Animals

Mice have a heart rate of over 500 beats perminute and an aorta that is 1 mm in diameter, butthey are a valid model for studying both pressure-overload hypertrophy and heart failure, because ofthe similarities of these disorders in mice and hu-mans.

12-14

The ability to engineer precise mutationsin the heart, coupled with the ability to quantitatethe effects of these mutations on cardiac functionin vivo,

15,16

has led to the recognition of a pre-viously unsuspected set of signaling pathways andmolecules that stimulate specific aspects of cardiacgrowth. The effects of both the overexpression andthe loss of individual cardiac genes in animals havebeen studied, and we will describe examples of each.These models are useful not simply because theyreplicate human disease but also because they allowthe differentiation of the many different processesthat together cause such conditions as pressure-

Figure 2.

Pathways Involved in Hypertrophy, Apoptosis, and Survival of Myocytes during the Transition between CardiacHypertrophy and Heart Failure in Response to Biomechanical Stress.

Biomechanical stress, such as chronic hypertension and pressure overload, activates multiple parallel and convergingsignals for hypertrophy and apoptosis, which represent two distinct outcomes. At the same time, biomechanical stress

also leads to the induction of gp130-dependent ligands, such as cardiotrophin 1. This cytokine binds to its receptor,which consists of gp130LIF (leukemia inhibitory factor) receptor heterodimers, resulting in the activation of down-stream gp130 pathways that block the actions of apoptotic pathways. In the absence of gp130, the response of cardiac

myocytes to biomechanical stress is shifted toward apoptosis, resulting in the loss of functional myocytes and the onsetof heart failure. Thus, the outcome of biomechanical stress is dependent on the balance between these two contradic-

tory signal-transduction pathways.

LIF receptorgp130

Compensatory hypertrophy Heart failure

Apoptotic signals

(Gqa, p38a)

ApoptosisOrganization of sarcomeres

Increased expression of

embryonic genes

Hypertrophic signals

(ras, Gqa, p38b)

Apoptotic signals

(Gqa, p38a)

ApoptosisOrganization of sarcomeres

Increased expression of

embryonic genes

Hypertrophic signals

(ras, Gqa, p38b)

Interleukin-6 family of cytokines

Pressure overload

Cardiac myocyte



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overload hypertrophy and congestive heart failure inhumans.

In the tissue-restricted approach to overexpression,the regulatory region from a cardiac-specific gene isfused to a candidate gene of interest and used toproduce transgenic mice that express the candidate

gene specifically in cardiac-muscle cells because ofthe ability of the regulatory sequences to restrict ex-pression to the heart.

17

The availability of well-char-acterized regulatory regions of cardiac-specific geneshas allowed the expression of candidate signaling mol-ecules in the heart and even in the ventricles alone.For example, transgenic mice have been producedthat express an active mutant of ras, a protein thatmediates many growth-related responses in cardiacmyocytes as well as in cancer cells.

18

Since the regu-latory sequences of a ventricle-specific gene controlthe expression of this active form of ras, the heart isthe only tissue in the animals in which the ras path-

ways are activated.

19,20

High levels of expression of

ras result in hypertrophic cardiomyopathy, includingmassive cardiac hypertrophy, heart failure, and sud-den death, but not the dilatation of any heart cham-ber (unpublished data). Increased concentrations ofras messenger RNA were recently described in en-domyocardial-biopsy specimens from humans withfamilial hypertrophic cardiomyopathy.

21

It is possible to disrupt, or target, a gene of inter-est in a mouse by replacing it with a mutated sequenceearly in embryogenesis.

22

Mice that are heterozygousfor the mutated allele can be mated to produce ho-mozygous mice that do not have a functional copyof the targeted gene. For example, mice with dele-tions of a muscle-restricted cytoskeletal protein have

features of dilated cardiomyopathy,

23

a finding thatsupports a causative role for disrupted cytoskeletoncomponents in the pathogenesis of cardiomyopathy.Since many structural and signaling components ofcardiac myocytes are common to other tissues, genetargeting may be lethal; the animals may die fromdefects in other tissues before the role of the genein the heart can be studied. This difficulty can nowbe avoided by techniques to engineer heart-specificgene deletions.

24,25

PRESSURE OVERLOAD AND CONCENTRIC

HYPERTROPHY

The extent of ventricular hypertrophy in patientsis a powerful predictor of adverse events. According-ly, identifying the signals that mediate the pathwaysfrom mechanical stress to downstream cellular eventshas been a major area of interest. Both myocytes andnonmyocytes are direct biomechanical sensors of he-modynamic load. Growth signals are generated bythe release of growth factors and cytokines, whichlead to a regionally localized response. The factorsthat have been implicated in this response includepeptides that stimulate G proteincoupled receptors

(endothelin-1

26,27

), angiotensin II,

28,29

interleukin-6related cytokines (cardiotrophin 1

30,31

), and growthfactors that activate receptor tyrosine kinases (insu-lin-like growth factor I

32,33

).One of the first genetically defined models of con-

centric ventricular hypertrophy resulted from cardiac-

directed overexpression of the a

1b

-adrenergic recep-tor.

34

This confirmed previous work in culturedcardiac myocytes demonstrating that a

-adrenergicstimulation induced a hypertrophic response. a

-Adre-nergic receptors share common intracellular signal-ing pathways with other hypertrophic growth fac-tors, including angiotensin II and endothelin-1. Ineach of these pathways, signaling that results in hy-pertrophy proceeds by means of the G

q

a

subunitof heteromeric G protein, which was found to beboth necessary and sufficient to cause hypertrophyin cultured cardiac-muscle cells.

35

Subsequently, over-expression of G

q

a

itself was found to induce botha hypertrophic and an apoptotic response.

36,37

Fur-

thermore, a protein inhibitor of G

q

a

, whose expres-sion was also targeted to the heart by transgenictechniques, had no effect on cardiac structure or func-tion in unstressed mice, but it prevented hypertro-phy when pressure overload was induced by con-stricting the ascending aorta.

38

Taken together, theseresults suggest that G

q

a

-dependent pathways have acritical role in the development of myocardial hy-pertrophy (Fig. 2).

The activation of cell-surface receptors and theirimmediate signaling targets, such as ras and G

q

a

, bycardiac growth factors is the first step in initiating thegrowth of myocytes (Fig. 2). Increases in intracellu-lar calcium concentrations in response to these growth

factors may also activate calmodulin-dependent path-ways.

39-41

According to in vitro and in vivo results,the primary downstream effectors are the mitogen-activated protein kinases, including c-jun N-terminalkinase and p38.

7,9,10,31

These kinases are particularlyimportant switches in the pathways between apop-tosis and adaptive hypertrophy. For example, in micep38 mitogen-activated protein kinases are stronglyactivated by pressure overload, and upstream kinasesthat specifically activate p38 cause the growth of cul-tured myocytes. However, the activation of p38 isalso accompanied by an increase in the rate of apop-tosis.

9

The two isoforms of p38, a

andb

, have oppo-site effects on apoptosis when stimulated by upstreamactivators: p38

a

increases apoptosis, whereas p38

b

inhibits it (Fig. 2).

9

CHAMBER DILATATION AND DILATED

CARDIOMYOPATHY

Dilated cardiomyopathy represents a final commonpathway of the myocardium in response to many dif-ferent pathologic conditions. This has led to the ob-

vious conclusion that there are common pathways tocardiac dilatation and failure. Local myocardial inju-



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ry can cause progressive and sometimes deleteriousdilatation and thinning of the ventricular wall.

In about 25 percent of patients with idiopathic di-lated cardiomyopathy, the disorder is familial and ge-netic, and it is likely to be genetic in some nonfamil-ial cases as well.

4

Indeed, the first example of familial

dilated cardiomyopathy for which the genetic basiswas defined was Duchennes muscular dystrophy. Inthis and related muscular dystrophies, the moleculardefect is in the dystrophindystroglycanlaminintransmembrane complex that connects the actin cy-toskeleton of the muscle cells to structural proteinsthat are synthesized by fibroblasts surrounding themyocytes (Fig. 3). In these dystrophies, there is animpairment of the normal linkage by which forcegenerated by individual myocytes is translated into

work done by the muscle tissue as a unit, and exces-sive stresses on individual myocytes cannot be spreadacross that muscle.

The recent demonstration that the molecular de-

fect in Syrian hamsters with cardiomyopathy lies inthe d

-sarcoglycan component of this complex

42

fur-ther implicates the linkage between the myocyte cy-

toskeleton and the extracellular matrix in the patho-genesis of cardiomyopathy. Moreover, a moleculardefect involved in familial dilated cardiomyopathy inhumans has been mapped to the cytoskeletal regionof the cardiac actin gene.

43

One of the first examplesof a genetic link between the cytoskeleton and dilat-

ed cardiomyopathy was provided by studies of micethat have a deficiency in a muscle-specific LIM (lin-1,ISL-1, and mec-3) domain protein

23

and have manyfeatures of the dilated cardiomyopathy that occurs inhumans. This cytoskeletal protein may be a compo-nent of a biomechanical sensor pathway that trans-duces hemodynamic force into specific signaling re-sponses. Disruption of other cytoskeletal proteins,such as desmin, plakoglobin, and N-cadherin, resultsin cardiac dilatation and impaired cardiac functionduring fetal development or after birth. In summary,increased biomechanical stress on cardiac myocytes,either through genetic abnormalities or through ex-cessive stress on the chamber wall due to myocyte loss

or severe hemodynamic loading, generates a persist-ent signal for ventricular growth and hypertrophy.

2,44

By contrast, mutations in sarcomeric proteins cause

Figure 3.

Primary Structural Components of the Linkage between the Cytoskeleton and the Extracellular Matrix, Includ-ing Actin, the DystrophinGlycoprotein Complex, and Laminin-2 (Merosin).

Genetic defects in these components lead to dilated cardiomyopathy, with or without associated skeletal myopathy.This complex is physically associated with the Z-disk of cardiac myocytes, the Z-disk components desmin (associatedwith dilated cardiomyopathy in humans and mice) and a-actinin, and a muscle-specific cytoskeletal protein (MLP) (as-sociated with dilated cardiomyopathy in mice).23 The question mark indicates an unknown factor.

Z-diskZ-disk

Extracellular matrix

Sarcoglycans

Dystroglycans

Dystrophin

Syntrophins

Desmin

Cytoskeletal

a-actin

Dystrophin

Syntrophins

Laminin-2

d g a

a

bb

a-Actinin

MLP

Desmin

Cytoskeletal

a-actin

?



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hypertrophic cardiomyopathy but do not affect ven-tricular systolic function.

Apoptosis of Cardiac Myocytes

Apoptosis is a mechanism by which cells can beeliminated without an inflammatory response. Evi-

dence of an increased rate of apoptosis has been de-tected in failing hearts at the time of transplantationin humans, as well as in hearts from animals with ex-perimentally induced hypertrophy and cardiomyop-athy. Unlike necrosis, apoptosis leaves little or nohistologic trace of the lost cells. Accordingly, docu-menting its occurrence and estimating the extent ofthe loss of myocytes as a result of apoptosis havebeen problematic; therefore, the importance of ap-optosis in the transition from compensatory hyper-trophy to heart failure has been unclear.

At the cellular level, there is normally a balance be-tween apoptotic and anti-apoptotic signals, and celldeath occurs in response to a persistent shift in this

balance. The cytokine tumor necrosis factor a, act-ing through its receptor, activates both apoptoticand anti-apoptotic signals, with a tendency towardpromoting apoptosis. Similarly, p21 ras induces bothapoptotic c-jun N-terminal kinase and anti-apoptotic1-phosphatidylinositol 3-kinase signals. Among mito-gen-activated protein kinases, the extracellular signalregulated kinases tend to be anti-apoptotic, c-junN-terminal kinase promotes apoptosis,8 and as men-tioned, the a andb isoforms of p38 have opposing

effects (Fig. 2).9 Cell death may occur when the ap-optotic forces exceed a certain threshold. The acti-

vation of apoptotic signals during the hypertrophicresponse of myocytes may explain the risk of deathassociated with ventricular hypertrophy in humans.In support of this concept, mice with a loss-of-func-

tion mutation in the cytokine receptor gp130 of theventricular chamber have normal cardiac structure buthave massive cardiac apoptosis accompanied by rap-idly progressive dilated cardiomyopathy when sub-

jected to pressure overload.25 These studies indicatethat the inhibition of apoptosis by gp130-dependentpathways in myocytes has a critical role in the tran-sition between compensatory hypertrophy and overtheart failure and suggest that the balance between ap-optotic and hypertrophic pathways determines wheth-er chamber dilatation will occur (Fig. 2).25

Cardiac Function and Contractility

The b-adrenergicreceptor pathway is a critical

point of control for cardiac contractility in both nor-mal and failing hearts (Fig. 4). The primary func-tional disturbance in dilated cardiomyopathy is im-paired contractility, yet when contractility is decreasedin mice by overexpression of the calcium-regulatoryprotein phospholamban, the mass and volume of thecardiac chamber are no different from those in nor-mal mice.46 Moreover, when contractility is decreased,as in mice with mutations in the myosin heavy chain,the result is hypertrophic cardiomyopathy, without

Figure 4. Regulation of the Contractile Function of Myocytes.

The contractile function of myocytes is regulated by changes in calcium flux into and out of the sarcoplasmic reticulum.Activation ofb-adrenergic receptors leads to increased uptake of calcium into the sarcoplasmic reticulum by the calcium

pump; the phosphorylation (P) of phospholamban by cyclic AMP-dependent protein kinase (PKA) removes its tonic in-hibition of the calcium pump. b-Adrenergic receptors are desensitized in both heart failure and maladaptive hypertro-phy; a substantial component in this desensitization is up-regulation of the b-adrenergicreceptor kinase (bARK). A de-

ficiency of phospholamban has recently been shown to halt the progression of heart failure and dilated cardiomyopathyin a genetically based animal model.45

b-Adrenergic

receptor kinase

Cyclic AMP

Adenylyl cyclase

PKA

GSaGSa

Phospho-lamban

P

CalciumCalcium pump

Sarcoplasmic

reticulum

b-Adrenergic

receptor kinase

Cyclic AMP

Adenylyl cyclase

PKA

Sarcoplasmic

reticulum

b-Adrenergic receptor



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chamber dilatation.47 These observations, as well asclinical and experimental studies ofb-adrenergicblocking drugs in patients with heart failure, suggestthat impaired contractility in certain forms of dilatedcardiomyopathy may be a secondary phenomenon,perhaps resulting from alterations in energy metab-

olism or intracellular calcium handling.Animals have been developed that have increased

ventricular contractile function as a primary feature.These include mice that overexpressb1- andb2-adre-nergic receptors48,49 or the Gsa protein to which it iscoupled50; mice that overexpress a peptide inhibitorof the b-adrenergicreceptor kinase, the principaldesensitizer ofb-adrenergic receptors51; and mice in

which the phospholamban gene has been disrupted.52

The increased risk of death among patients with heartfailure that is associated with chronic stimulation ofb-adrenergic agonists can be replicated in mice withdilated cardiomyopathy due to a cytoskeletal genemutation.23 The offspring of genetic crosses between

these mice23 and those overexpressingb2-adrenergicreceptors49 have a very high mortality rate.53 How-ever, a genetic cross between the cardiomyopathicmice23 and those overexpressing the peptide inhibi-tor of the b-adrenergicreceptor kinase results in amouse with decreased chamber dimensions and im-proved contractile function.53 This suggests that thedeleterious effect of long-term exposure to inotropicdrugs, such as phosphodiesterase inhibitors, in pa-tients with heart failure may not be due to changesin contractility alone.53 The different effects of over-expression of theb2-adrenergic receptor and overex-pression of the inhibitor of the b-adrenergicrecep-tor kinase might also reflect differing downstream

effects on cardiac relaxation,54 or pathologic effectsof chronicb-adrenergic overstimulation48 as compared

with those resulting from relief of desensitization.53

In this regard, phospholamban negatively regulatesthe uptake of calcium by the sarcoplasmic reticulum(Fig. 4), and a deficiency of phospholamban can haltprogression of dilated cardiomyopathy and heart fail-ure.54b-Adrenergic pathways lead to the phospho-rylation of phospholamban, which reduces its activ-ity and increases ATPase activity in the sarcoplasmicreticulum.

CONCLUSIONS

The decrease in cardiac performance in the failing

heart may be a consequence of alterations in specificsignaling molecules and their downstream pathwaysin individual myocytes (Table 1). By analogy to car-cinogenesis, heart failure may be viewed as a pro-gressive, multistep process involving physiologic andmolecular initiators, promoters, suppressors, and ef-fectors of the chronic course to heart-muscle failure.7

Further unraveling of the signals that cause specificfeatures of heart failure, coupled with the growinghuman genome data base, should ultimately lead to

the identification of targets whose actions could beinterrupted, thereby halting or perhaps reversing clin-ical deterioration.

REFERENCES

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Saunders, 1999:211-50.8. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposingeffects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995;270:1326-31.9. Wang Y, Huang S, Sah VP, et al. Cardiac muscle cell hypertrophy andapoptosis induced by distinct members of the p38 mitogen-activated pro-tein kinase family. J Biol Chem 1998;273:2161-8.10. Wang Y, Su B, Sah VP, Brown JH, Han J, Chien KR. Cardiac hyper-trophy induced by mitogen-activated protein kinase kinase 7, a specific ac-tivator for c-Jun NH2-terminal kinase in ventricular muscle cells. J BiolChem 1998;273:5423-6.11. Sah VP, Hoshijima M, Chien KR , Brown JH. Rho is required for Gal-phaq and alpha1-adrenergic receptor signaling in cardiomyocytes: dissoci-ation of Ras and Rho pathways. J Biol Chem 1996;271:31185-90.12. Chien KR. Genes and physiology: molecular physiology in geneticallyengineered animals. J Clin Invest 1996;97:901-9.13. Rockman HA, Ross RS, Harris AN, et al. Segregation of atrial-specificand inducible expression of an atrial natriuretic factor transgene in anin vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci U S A

1991;88:8277-81. [Erratum, Proc Natl Acad Sci U S A 1991;88:9907.]14. Rockman HA, Ono S, Ross RS, et al. Molecular and physiological al-terations in murine ventricular dysfunction. Proc Natl Acad Sci U S A1994;91:2694-8.15. Lin MC, Rockman HA, Chien KR. Heart and lung disease in engi-neered mice: technological miniaturization combined with the power ofmolecular genetics makes the mouse a model animal for understanding hu-man cardiovascular and pulmonary disease. Nat Med 1995;1:749-51.16. Christensen G, Wang Y, Chien KR. Physiological assessment of com-plex cardiac phenotypes in genetically engineered mice. Am J Physiol 1997;272:H2513-H2524.17. Hunter JJ, Zhu H, Lee KJ, Kubalak S, Chien KR. Targeting gene ex-pression to specific cardiovascular cell types in transgenic mice. Hyperten-sion 1993;22:608-17.18. Thorburn A, Thorburn J, Chen SY, et al. HRas-dependent pathwayscan activate morphological and genetic markers of cardiac muscle cell hy-pertrophy. J Biol Chem 1993;268:2244-9. [Erratum, J Biol Chem 1993;268:16082.]19. Hunter JJ, Tanaka N, Rockman HA, Ross J Jr, Chien KR. Ventricular

expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy andselective diastolic dysfunction in transgenic mice. J Biol Chem 1995;270:23173-8.20. Gottshall KR, Hunter JJ, Tanaka N, et al. Ras-dependent pathways in-duce obstructive hypertrophy in echo-selected transgenic mice. Proc Natl

Acad Sci U S A 1997;94:4710-5.21. Kai H, Muraishi A , Sugiu Y, et al. Expression of proto-oncogenes andgene mutation of sarcomeric proteins in patients with hypertrophic cardio-myopathy. Circ Res 1998;83:594-601.22. Young SG, Lusis AJ, Hammer RE. Genetically modified animal mod-els in cardiovascular research. In: Chien KR, ed. Molecular basis of cardio-

vascular disease: a companion to Braunwalds Heart Disease. Philadelphia:W.B. Saunders, 1999:37-85.23. Arber S, Hunter JJ, Ross J Jr, et al. MLP-deficient mice exhibit a dis-



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Señales moleculares de hipertrofia cardíaca

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