J Mol Cell Cardiol 32, 1381–1384 (2000)

doi:10.1006/jmcc.2000.1202, available online at http://www.idealibrary.com on

Editorial

Many Pathways to Cardiac HypertrophySusan F. SteinbergDepartments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University,NY 10032, USA

(Received 13 June 2000, accepted 13 June 2000)

A variety of pathologic stresses lead to cardiac The presence of functional and genetic correlatesto morphologically distinct forms of hypertrophyhypertrophy as an adaptive response to optimize

contractile performance. The general tendency in in vivo suggests that these phenotypes are encodedby distinct signaling cascades.1 However, hy-the literature has been to consider cardiomyocyte

hypertrophy as a single entity with grossly similar pertrophic syndromes have yet to be classified onthe basis of their distinct signaling mechanisms.outward morphologic and molecular mani-

festations. However, this ignores the evidence Since cardiac hypertrophy in vivo is the in-tegrated consequence of mechanical, electrical,that stimulus-specific differences in hypertrophic

growth responses in vivo can impact importantly and neurohormonal signals, many investigatorshave turned to in vitro cardiac cultures to dis-on prognosis. For example, contractile performance

is preserved during the physiologic hypertrophy tinguish the role of individual mechanochemicalsignals in the genesis of hypertrophic growth.that results from properly designed endurance

exercise training. In contrast, prolonged pathologic Indeed, the cardinal features of the distinct formsof cardiac hypertrophy encountered in clinicalstresses lead to an irreversible form of cardiac

hypertrophy that often undergoes transition to practice have been simulated in cultured car-diomyocytes. For example, the Gq-coupled �1-heart failure and represents a major risk factor for

subsequent cardiac death. Even in the pathologic adrenergic receptor induces a morphology andpattern of embryonic gene expression typical ofcontext, different forms of cardiac hypertrophy

can be broadly defined on the basis of structural in vivo pressure-overload. �1-adrenergic receptorsactivate a wide array of intracellular secondand molecular criteria. Chronic pressure-overload

(as typically seen in hypertension) induces “con- messenger molecules. Many of these have beenimplicated in at least some features of the hy-centric” cardiac hypertrophy, with grossly in-

creased wall thickness and little to no chamber pertrophic response when the stimulus is intense(i.e. in overexpression models, in some cases withenlargement. Cardiomyocytes display an increase

in cross-sectional area relative to cell length, with constitutively activated forms of the molecule);their precise contribution to catecholamine-sarcomeres added in parallel. In contrast, volume-

overload (as occurs with valvular incompetence) dependent molecular and morphological re-modeling of the heart remains actively disputed.2results in “eccentric” hypertrophy (i.e. a dis-

proportionately large increase in chamber volume Cardiotrophin-1 also induces hypertrophy throughthe gp130/leukemia inhibitory factor receptor.and relatively little increase in wall thickness).

Here, sarcomere deposition is in series, leading to Here, the constellation of morphologic and mo-lecular changes is more characteristic of volume-an increase in cell length in excess of cell width.

Please address all correspondence to: Susan F. Steinberg, M.D., Associate Professor of Pharmacology and Medicine, Department ofPharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168 Street, New York, NY 10032, USA. E-mail:sfs1@columbia.edu

0022–2828/00/081381+04 $35.00/0 2000 Academic Press

S. F. Steinberg1382

overload;3 a similar morphology is induced by cardiomyocyte hypertrophy.12–15 The most readilydetected calcium-sensitive PKC isoform in car-agonists for protease-activated receptor-1.4 Car-

diotrophin-1 and �1-adrenergic receptor agonists diomyocyte preparations is PKC� (its abundanceapproximately eight-fold greater than the calcium-share certain signaling pathways, but there also

are clear differences, suggesting that the molecular insensitive PKC� isoform in rat cardiomyocytecultures).16 A rise in calcium in the contextor morphological signature of any hypertrophic

phenotype is dictated by the precise balance of of phospholipase C activation promotes PKC�activation in non-cardiomyocytes. Calcium is re-signaling pathways activated by that stimulus.

Electrical pacing was first identified as a stimulus ported to play an ill-defined role upstream in thepurinergic receptor pathway for phosphorylation/leading to cardiomyocyte growth in serum-free

conditions in the early 1990s.5,6 A series of studies activation of phospholipase C (PLC)� in car-diomyocytes.17 Nevertheless, pacing-induced el-spread across several laboratories and spanning

eight years subsequently described the features evations in calcium neither stimulatephospholipase C nor activate PKC� in rat car-of electrical pacing-induced hypertrophy as an

increase in cardiomyocyte size and protein content, diomyocyte cultures.5 Rather, Strait and Samareldemonstrate that electrical pacing selectively ac-enhanced atrial natriurectic factor (ANF) secretion,

induction of various immediate early genes (c-fos, tivates novel PKC� and PKC� isoforms. This raisestwo questions. First, how do nPKC isoformsc-jun, junB), and transcriptional activation of

certain embryonic genes [ANF, �-myosin heavy become activated? In the absence of any evidencethat pacing mobilizes the conventional phos-chain (�-MHC), and myosin light chain-2 (MLC-

2)].5–9 Studies by Xia et al. place particular pholipase C pathway, other mechanisms must beconsidered. A recent study demonstrating thatemphasis on cardiac pacing as a model of increased

energy demand, resulting in mitochondrial pro- mitochondrial superoxide overproduction is a stim-ulus for PKC activation in vascular endotheliumliferation/maturation and transcriptional ac-

tivation of respiratory genes (cytochrome oxidase is particularly provocative in the context ofevidence that electrical pacing increases mito-subunit Va, cytochrome c).8–10 In this context,

the study by Strait and Samarel in this issue of chondrial biogenesis and up-regulates respiratorygenes.18 Second, why isn’t PKC� activated? Thethe Journal of Cellular and Molecular Cardiology

identifies effects of contractile calcium transients consensus of studies using cell fractionation andWestern blot analysis is that various hypertrophicto increase cell size, protein content, and �-MHC/

ANF expression.11 Structural and genetic features stimuli (including those that elevate intracellularcalcium) selectively activate nPKC isoforms (andthat have been used to distinguish various forms

of hypertrophy were not included in this or not PKC�).19 Admittedly, translocation as a hall-mark for PKC isoform activation may be imperfect,previous studies, precluding any predictions as to

whether pacing-induced hypertrophy simulates as enzyme activation without a stable change inits subcellular distribution at least in theory isthe adaptive/physiologic or maladaptive/patho-

logic response. possible. Nevertheless, these results have fueledspeculation that cardiomyocytes (with a largeSeveral laboratories have attempted to identify

potential mechanisms for pacing-induced car- molar excess of PKC� over PKC�) possess a cell-specific mechanism to render PKC� particularlydiomyocyte growth. Since electrical pacing induces

a rise in intracellular calcium (one of the earliest refractory to activation by physiologic oscillationsof calcium. Compartmentalization of calcium poolssignals implicated in cardiac hypertrophy), it was

intuitively reasonable to postulate that calcium- could provide such a mechanism, but concreteexperimental evidence is still lacking.dependent hypertrophic signaling pathways might

be important. Indeed, the earliest studies by Another set of signals that have been the focusof particularly intense attention (given their import-McDonough et al. demonstrated that ANF (a

marker of cardiac hypertrophy) is induced by ance in controlling the proliferation of dividingcells) are mitogen-activated protein kinase (MAPK)contractile calcium transients in a manner that

requires calmodulin and Ca2+/calmodulin-de- cascades. These consist of three three-memberedprotein kinase cascades, whose final componentspendent protein kinase II activity.5,7 Subsequent

studies by Allo et al. suggested a role for protein are the extracellular-signal regulated kinase (ERK),c-Jun N-terminal kinase (JNK), and p38-MAPK.kinase C (PKC) on the basis of evidence that

electrical pacing increases nuclear PKC activity.6 All three MAPKs have been implicated in cardiachypertrophy, but many aspects of the results remainPKC is a family of calcium-sensitive and calcium-

insensitive isoenzymes, with several implicated in highly disputed.2 ERK activation accompanies

Many Pathways to Cardiac Hypertrophy 1383

hypertrophic responses to endothelin, �1-adrenergic Finally, there is evidence that the Ca/CaM-de-pendent phosphoprotein phosphatase calcineurinreceptor agonists, cardiotropin-1, mechanical

stretch, and virtually every other form of car- also is a mediator of pacing-induced hypertrophy.26

Calcineurin dephosphorylates NFAT transcriptiondiomyocyte activation. Indeed, stimulus-inducedERK activation is so very widespread that the iden- factors, facilitating their translocation from the cy-

tosol to the nucleus where they can cooperate withtification of a stimulus that fails to recruit the ERKcascade is the greater challenge (although see Ref the GATA4 pathway to activate target genes. Of

note, pacing-dependent induction of �-MHC and20). Calcium is among the many cellular mech-anisms that have been implicated in ERK activation other genes involved in cardiac energy metabolism

is via this calcineurin-dependent pathway, whereasin cardiomyocytes.21 Therefore, the consistentevidence from two laboratories that ERK is not immediate early genes such as c-fos are induced

via a calcineurin-independent mechanism.8 Thisactivated during the first hour electrical pacingcomes as a surprise. However, this result is in- emphasizes the complex and integrated nature of

cardiac hypertrophic signaling networks. Yet, muchformative for two reasons. First, the observationthat electrical pacing induces cell growth and ANF of our current knowledge regarding the regulation

of cardiac is derived from studies that attempt aexpression, without activating ERK, argues thatERK is not an absolute prerequisite for the ac- reductionist approach (i.e. pharmacologic stimu-

lation by a single agonist/molecule) in cardiac cul-quisition of these features of the hypertrophicphenotype (although the unlikely possibility that tures. While this approach identifies potential

independent functions of individual intracellularERK activation might be detected coincident withhypertrophic changes at a later time point cannot signals (and, therefore, is likely to remain the cor-

nerstone of strategies to identify potential thera-be excluded). Second, the failure to detect ERKactivation during electrical pacing distinguishes the peutic targets), it fails to respect adequately the

vast amount of information that is encoded bypacing model from mechanical stretch, where ERKactivation (due to autocrine/paracrine actions of physiologic differences in the kinetics and/or am-

plitude of signaling molecule activation. Its rel-angiotensin II and endothelin) is prominent.22 Theresults argue that pacing-induced hypertrophy does evance to the physiologic setting, where many

agonists act in concert at subsaturating con-not result from the actions of growth factors secretedinto the culture medium. centrations to remodel the heart must be interpreted

with caution. In this context, studies of PKC, JNK,The experiments of Strait and Samarel also con-firm previous evidence that electrical pacing ac- and calcineurin activation during electrical pacing

interrogate the function of the endogenous sig-tivates JNK.23 Electrical pacing-induced JNKactivation is a calcium-sensitive process and is spe- naling machinery (without altering the stoi-

chiometry of any individual component of thecific for the JNK2 and JNK3 isoforms. Currently,there is only rudimentary knowledge of upstream signaling cascade) and play to the strength of the

culture model as an assay system. To the extentactivators of JNK in cardiomyocytes. Since electricalpacing activates PKC, and pharmacologic activation that pacing-induced hypertrophy displays certain

unique biochemical features (i.e. activation of onlyof PKC with phorbol esters leads to modest JNKstimulation, two groups of investigators attempted certain PKC/JNK isoforms, and not ERK), it also

may constitute an under-appreciated resource toto implicate PKC in electrical pacing-induced JNKactivation.7,11 However, these experiments em- delineate the hierarchical organization of second

messenger pathways that mediate the molecularployed chelerythrine as a pharmacologic PKCantagonist, an unfortunate choice given recent evi- and morphologic features of cardiomyocyte growth.

Finally, it is tempting to speculate that pacing-dence that chelerythrine is a potent activator ofp38-MAPK and JNK pathways.24 The full con- induced hypertrophy might be a surrogate for one

of the forms of hypertrophy encountered in clinicalsequences of JNK activation also are uncertain.McDonough et al. reported that collaborative inter- practice and therefore a particularly informative

model for a specific clinical hypertrophy syndrome.actions between JNK, its substrate c-Jun, serum-response factor, and Sp1 lead to calcium-dependenttranscriptional activation of ANF.23 Other literaturesupports the seemingly contradictory conclusions Acknowledgementsthat JNK induces cardiomyocyte hypertrophy orpromotes apoptosis. Whether this can be attributed This work was supported by U.S.P.H.S.-N.H.L.B.I.

grant HL-28958 and American Heart Associationto isoform-specific signaling by JNK (as describedfor p38-MAPK)25 has not been considered. Grant-in-Aid.

S. F. Steinberg1384

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