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Cardiovascular Research 2004 63(3):500-509; doi:10.1016/j.cardiores.2004.03.015
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Copyright © 2004, European Society of Cardiology

Negative regulators of cardiac hypertrophy

Stefan E Hardta,b and Junichi Sadoshima*,a

aDepartment of Cell Biology and Molecular Medicine, UMDNJ, Cardiovascular Research Institute, 185 South Orange Avenue, MSB G-609, Newark, NJ 07103-2714, USA
bDepartment of Cardiology, University of Heidelberg, Heidelberg, Germany

* Corresponding author. Tel.: +1-973-972-8619; fax: +1-973-972-8919. Email address: sadoshju{at}umdnj.edu

Received 30 January 2004; revised 10 March 2004; accepted 11 March 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
 5. Trx1
 6. Therapeutic implications
 References
 
Throughout the past decade, much effort has been spent on deciphering the signaling pathways positively mediating cardiac hypertrophy. Recently, several endogenous molecules in the heart have been shown to negatively regulate cardiac hypertrophy. One group of these molecules is constitutively active at baseline, while molecules belonging to the second group serve as negative feedback regulators, which are activated in response to pathologic insults. Studies upon the negative regulators of cardiac hypertrophy may allow us to develop novel strategies to treat heart failure by mimicking the naturally preferred mechanisms to maintain homeostasis. In addition, the search for molecular targets of these negative regulators may allow us to identify novel positive mediators of hypertrophy. The aim of this article is to provide a brief overview of these newly identified negative regulators of cardiac hypertrophy.

KEYWORDS Hypertrophy; Signal transduction; Negative regulation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
 5. Trx1
 6. Therapeutic implications
 References
 
Left ventricular hypertrophy (LVH) is a well-established risk factor for cardiovascular mortality [1–5]. If untreated, LVH leads to systolic and diastolic cardiac dysfunction and ultimately induces heart failure. LVH is characterized by an increase in the cell size and protein content of cardiac myocytes as well as reactivation of the fetal gene program, such as expression of atrial natriuretic factor (ANF). During the past decade, much effort has been focused on deciphering signaling pathways positively mediating cardiac hypertrophy [6–8]. Despite significant progress in our knowledge about the signaling mechanism of hypertrophy, cardiovascular disease is still the leading cause of death in western countries [9]. Traditional pharmacotherapy targeting the prohypertrophic pathways, such as angiotensin converting enzyme (ACE) inhibitors and β-adrenergic receptor (β-AR) blockers, can reduce hypertrophy substantially, but not completely [10]. In this regard, exploration of another therapeutic modality effectively inhibiting pathologic forms of cardiac hypertrophy seems essential. To this end, increasing lines of evidence suggest that identifying the mechanisms counteracting hypertrophy might be as important as investigating the mechanisms leading to cardiac hypertrophy. Several endogenous molecules have been shown to negatively regulate cardiac hypertrophy; upregulation of these molecules inhibits cardiac hypertrophy, while downregulation of them rather stimulates hypertrophy. The aim of this article is to provide a brief overview of the endogenous negative regulators of cardiac hypertrophy. We also discuss potential applications of targeting these negative regulators for treatment of cardiac hypertrophy and heart failure.


   2. Classifications of inhibitors of cardiac hypertrophy
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
3. GSK-3β
 4. ICER
 5. Trx1
 6. Therapeutic implications
 References
 
In Table 1, we provided examples of negative regulators of hypertrophy. We included a molecule in this category only when the endogenous molecule present in the heart has been shown to inhibit cardiac hypertrophy. In other words, molecules, such as ATP [11], CHAMP [12] and retinoic acid [13–15], which inhibit hypertrophy only when they are introduced exogenously or overexpressed were excluded. For these molecules, further examination, including the loss of function study, is needed to classify them as endogenous regulators of cardiac hypertrophy. Therefore, the list of these examples of negative regulators is likely to grow in the near future. Although the molecular nature of the molecules listed is diverse, they can be classified into two categories, depending upon when they are activated with respect to the timing for the development of hypertrophy (Fig. 1).


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  		Table 1 Endogeneous negative regulators of cardiac hypertrophy

 

Figure 1
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  		Fig. 1 Group I negative regulators of hypertrophy are active at baseline and become inactive under hypertrophic stimuli, which leads to unopposed cardiac hypertrophy (left panel). In contrast, expression or activities of group II negative regulators of hypertrophy are low at baseline, but upregulated in response to hypertrophic stimuli, and counteract prohypertrophic stimuli (middle). Combined actions of group I and group II negative regulators maintain balance between antihypertrophic and prohypertrophic activities at baseline and during well-compensated hypertrophy. Progressive hypertrophy develops when hypertrophic stimuli dominate (right panel). Therapeutic interventions may allow group I and group II negative regulators to balance antihypertrophic and prohypertrophic activities at baseline and in the presence of hypertrophic stimuli.

 
The first group consists of constitutively active molecules, including glycogen synthase kinase-3β (GSK-3β), class II histone deacetylases (HDACs), thioredoxin (Trx1), caveolin-3 and phospholipase A2. These molecules are expressed and active even in unstimulated cardiac myocytes. Experimentally, the negative influence of these molecules upon cardiac hypertrophy at baseline is manifested either when the activity of the molecule is inhibited or when expression of the molecule is downregulated by loss of function approaches. For example, inhibition of GSK-3β induces hypertrophy by removing its constitutive inhibitory effects upon hypertrophy [16]. As we discuss below, GSK-3β is a unique serine/threonine kinase, which is active even in unstimulated cardiac myocytes. Similarly, HDAC9, a class II HDAC, localizing at the nucleus, negatively affects MEF2, thereby inhibiting cardiac hypertrophy, while nuclear exit of HDAC9 by a stress-responsive kinase-dependent mechanism removes negative constraint of HDAC9 upon hypertrophy and stimulates hypertrophy [17]. Furthermore, selective inhibition of Trx1, an antioxidant, by overexpression of dominant-negative Trx1 in the heart causes cardiac hypertrophy [18]. It is likely that these molecules are required in order to counteract prohypertrophic mechanisms, which are always active even at baseline in the heart. For example, GSK-3β phosphorylates NF-ATs, GATA4, β-catenin, transcription (co)factors, and eIF2B{varepsilon}, a regulatory factor of protein translation, thereby suppressing their prohypertrophic effects by keeping them away from the nucleus or simply rendering them inactive [19–23]. The unique function of HDAC9 is to inactivate MEF2, a powerful prohypertrophic transcription factor constitutively expressed in the nucleus of adult cardiac myocytes [17]. Reactive oxygen species are constantly produced through leakage from the mitochondrial electron transport chain and stimulate hypertrophy [24,25]. Identifying the mechanisms negatively regulating the constitutive prohypertrophic mechanisms has several implications for heart failure research. First, inhibition of a constitutively active negative regulator can be the cause of cardiac hypertrophy. In fact, either enzymatic activities or protein expression of these negative regulators is altered in various pathophysiological conditions. Upregulation as well as downregulation of these molecules during heart failure or in response to pharmacotherapy may affect the prognosis of the patients. Second, elucidating the signaling mechanism targeted by a negative regulator of cardiac hypertrophy may lead to identification of a critically important mechanism positively mediating cardiac hypertrophy. As we discussed above, these molecules may exist in order to mitigate otherwise strong prohypertrophic mechanisms. Thus, the search for the molecular targets of these negative regulators may allow us to identify a fundamental positive mediator of cardiac hypertrophy.

The second group of negative regulators of hypertrophy consists of molecules, which are activated and/or upregulated upon induction of hypertrophy, and work as a negative feedback regulator, including inducible cAMP early repressor (ICER), MCIP-1, ANP/BNP, SOCS-3 etc. Some molecules belonging to the first group of negative regulators, such as thioredoxin, can be included in this group if expression or activation can be induced and their antihypertrophic effects are enhanced by hypertrophic stimuli. Some molecules categorized in this second group can be included also in the first group as long as the antihypertrophic role at baseline can be proven by genetic deletion experiments. Negative feedback regulation takes place at various stages of signal transduction. Thus, some negative regulators acting at proximal points of hypertrophy-signaling mechanisms would reverse broad aspects of cardiac hypertrophy whereas others at distal points may antagonize only specific aspects of hypertrophy. In this regard, it is important to identify individual hypertrophy-associated phenotypes affected by each negative feedback regulator of hypertrophy.

It should be noted that in many pathophysiological contexts combined actions of group I and group II molecules maintain the homeostasis of cardiac myocyte growth. When the hypertrophic stimulus is predominant over endogenous negative regulators, hypertrophy develops (Fig. 1, right panel).

In the following, we will summarize recent findings of representative negative regulators of cardiac hypertrophy. We focused on three molecules, namely, GSK-3β representing the first group of negative regulator, ICER representing the second group, and thioredoxin, which belongs to both groups.


   3. GSK-3β
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
4. ICER
 5. Trx1
 6. Therapeutic implications
 References
 
Glycogen synthase kinase (GSK-3) belongs to a family of conserved serine/threonine kinases. Although GSK-3β was initially described for its function to inhibit glycogen synthesis through phosphorylation of glycogen synthase [26], GSK-3β has been found to regulate a wide range of cellular functions, including gene expression, protein translation, and cytoskeletal integrity [27]. Recent studies from several laboratories have suggested that GSK-3β is an important endogenous negative regulator of cardiac hypertrophy [16,20–23,28–30]; that means, endogenous GSK-3β persistently prevents hypertrophy in unstimulated myocytes. Although GSK-3β is active even in unstimulated cardiac myocytes, LiCl treatment [21] or stimulation of β-adrenergic receptors [22,23], Gq-coupled receptors [21], and FAS receptor [16] leads to inactivation of endogenous GSK-3β. This prevents GSK-3β from executing its inhibitory effects on hypertrophy, thereby stimulating hypertrophy. Thus, GSK-3β is a typical example of the molecules belonging to the first group of the negative regulators of hypertrophy. Cardiac-specific overexpression of a constitutively active form of GSK-3β in transgenic mice inhibits hypertrophy by aortic banding and isoproterenol stimulation and partially prevents cardiac hypertrophy caused by an activated form of calcineurin [28,29]. Lack of FAS receptor-induced inhibition of GSK-3β by pressure overload in lpr mice, which do not have functional FAS receptors, coincided with rapid-onset left ventricular dilatation and heart failure due to the absence of compensatory hypertrophy [16]. These in vivo results also suggest an important role of GSK-3β in regulating cardiac hypertrophy.

GSK-3β mediates antihypertrophic effects through multiple mechanisms (Fig. 2). For example, GSK-3β phosphorylates a wide variety of transcription factors, thereby causing ubiquitination, nuclear exit, or decreases in the DNA binding, leading to decreases in nuclear transcription. For example, GSK-3β phosphorylates NF-AT and GATA4, thereby causing nuclear exit of these factors, while inhibition of GSK-3β by endothelin-1 and isoproterenol decreases phosphorylation of NF-AT and GATA4, respectively, thereby enhancing nuclear localization of these transcription factors and stimulating hypertrophy [21,22]. One of the critical steps controlling protein translation, a key feature of hypertrophy, is the binding of eukaryotic translation initiation factor 2 (eIF2) to the activated initiator tRNA (met-tRNAmet) and subsequent formation of a ternary complex that binds to the 40S ribosomal subunit. eIF2B{varepsilon}, the key subunit of eIF2B, controls GDP/GTP exchange reaction of eIF2, and its activity is negatively regulated by phosphorylation at Ser 540 [31]. A recent study from our laboratory indicated that inhibition of protein translation initiation through phosphorylation of eIF2B{varepsilon} is an important mechanism mediating antihypertrophic effects of GSK-3β [32]. GSK-3β also negatively regulates protein expression of β-catenin and cyclin D1 [33,34], through enhancement of proteasome degradation or changes in subcellular localization, which have been proposed to affect cardiac hypertrophy [30,35].


Figure 2
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  		Fig. 2 Proposed mechanisms leading to antihypertrophic effects of GSK-3β. GSK-3β affects many aspects of cardiac hypertrophy, including transcription, protein translation, and cytoskeletal organization. Phosphatidylinositol 3-kinase (PI3K); Ca2+/calmodulin (Ca2+/CaM); glycogen synthase kinase 3β (GSK-3β); Ca2+/calmodulin-dependent protein kinase (CaM Kinase); mitogen-activated protein kinase (MAPK); nuclear factor of activated T-cells (NF-AT); myocyte-enhancer factor 2 (MEF2); microtubule-associated protein (MAP); eukaryotic initiation factor 2B{varepsilon} (eIF2B{varepsilon}); eukaryotic initiation factor 4E-binding protein (4E-BP); eukaryotic elongation factor 2 (eEF2).

 
Although cardiac-specific overexpression of GSK-3β in transgenic mice inhibits hypertrophy [28,29], it is unclear whether or not stimulation of GSK-3β is salutary for patients with cardiac hypertrophy. GSK-3β stimulates apoptosis and increases phosphorylation of microtubule protein tau in neurons, which is closely related to the pathogenesis of Alzheimer disease [36]. Furthermore, salutary effects of LiCl for treatment of manic depression are attributed in part to its inhibitory effects upon GSK-3β in neurons [37]. Thus, it will be interesting to determine whether or not GSK-3β has cell protective effects on cardiac myocytes. Inhibition of GSK-3β has a cardioprotective effect in response to ischemia/reperfusion in rats [38], suggesting that GSK-3β may be detrimental in ischemic hearts. The kinase activity of GSK-3β is reduced in heart failure patients [39]. It has been recently shown that the active form of GSK-3β is enhanced when pressure overload-induced hypertrophy is blocked in mice deficient in melusin, a molecule interacting with β1 integrin [40]. In this case, GSK-3β activation and subsequent inhibition of hypertrophy could be detrimental because more animals die in response to pressure overload. It is therefore possible, that decreases in the GSK-3β activity contribute to either compensatory hypertrophy or cell survival in heart failure patients. In any case, further investigation will be required to elucidate whether downregulation of GSK-3β is the cause of heart failure (due to excess hypertrophy) or the compensatory response. Addressing this issue seems essential in order to determine whether we should stimulate or inhibit GSK-3β in heart failure patients.


   4. ICER
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
5. Trx1
 6. Therapeutic implications
 References
 
Increased production of cAMP by enhanced activities of adenylyl cyclase upon β-AR stimulation leads to activation of protein kinase A (PKA), which in turn causes phosphorylation and subsequent activation of cAMP response element (CRE) binding protein (CREB) and leads to gene expression through CRE-mediated transcription [41]. ICER is a member of the CREB and CRE modulator (CREM) family of transcription factors, which binds to CREs [42]. ICER has a DNA-binding domain identical to the one in CREM but lacks the transactivation domain, and therefore serves as a dominant negative for CREM/CREB-mediated transcription [42]. Expression of ICER is upregulated in an inducible manner when an internal promoter of the CREM gene, containing CRE sites, is stimulated by increased levels of cAMP or intracellular Ca2+ [42]. Expression of ICER is rapidly induced by β-AR stimulation in cardiac myocytes (Fig. 3) [43,44]. As expected from its function as a nuclear antagonist of CRE, overexpression of ICER significantly inhibits β-adrenergic cardiac hypertrophy [44], while antisense inhibition of endogenous ICER enhances β-adrenergic increases in protein/DNA content and ANF transcription [44]. These properties of ICER clearly fulfill the criteria as a negative feedback regulator of β adrenergic hypertrophy. Because expression of dominant-negative CREB mimicked the effect of ICER on β-adrenergic cardiac hypertrophy [45,46], ICER negatively regulates cardiac hypertrophy at least in part by inhibiting transcription through CREB/CRE. Because ICER negatively regulates expression of tyrosine hydroxylase, the rate-limiting enzyme for catecholamines biosynthesis [47,48], as well as β-ARs in glioma cells [49], ICER may also initiate a negative feedback mechanism at the level of ligand binding to the β-ARs. A unique aspect of this negative regulator in cardiac myocytes is, however, that ICER positively mediates apoptosis by β-AR stimulation [44]. The proapoptotic effects of ICER seem to be mediated by downregulation of Bcl-2 [44]. While it has been shown that cardiac-specific overexpression of dominant-negative CREB in transgenic mice causes dilated cardiomyopathy [45], the long-term effects of ICER upon cardiac myocyte hypertrophy and apoptosis remain to be determined in vivo [50].


Figure 3
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  		Fig. 3 ICER belongs to the group II negative regulators of cardiac hypertrophy and serves as a negative feedback-regulator of β-adrenergic cardiac hypertrophy. ICER is upregulated by β-adrenergic stimulation through CRE-dependent mechanisms. ICER in turn inhibits CRE-mediated transcription. ICER causes downregulation of β-ARs. ICER also inhibits its own expression. Importantly, ICER induces apoptosis, which is mediated by downregulation of the antiapoptotic molecule Bcl-2. Thus, ICER is a negative regulator of hypertrophy and a positive regulator of apoptosis in response to β-AR stimulation.

 

   5. Trx1
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
 5. Trx1
6. Therapeutic implications
 References
 
Keeping an equilibrium of the redox status of cells is important for cell survival and homeostasis of the cellular metabolism [51,52]. Although cells are maintained in reducing conditions under physiological conditions, production of reactive oxygen species is enhanced in response to pathologic stimuli, which increase oxidative stress in cells [24,25,53]. In order to maintain a homeostasis of the redox state, cells have antioxidant mechanisms including superoxide dismutase, catalase, glutathione and Trx. Trx1 is a 12-kDa protein with a redox-active disulfide/dithiol within the conserved active site. Trx1, Trx reductase and NADPH compose the Trx system, which functions as a protein–disulfide oxidoreductase system (Fig. 4) [54–56]. Oxidative stress modifies proteins with redox-sensitive cysteine residues [54,57] and leads to a predominance of disulfides rather than free thiol. The cysteine-targeted oxidation process is called S-thiolation and affects the function of the protein and intracellular-signaling mechanisms [24,57]. Trx1 reduces intracellular proteins with disulfides through its disulfide oxidoreductase activity [54]. Trx1 also interacts directly with various intracellular-signaling molecules and transcription factors, thereby affecting cell growth and cell survival in several cell types [54,55].


Figure 4
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  		Fig. 4 Continuous production of reactive oxygen species in the heart is in part antagonized by Trx1. Increases in oxidative stress by hypertrophic stimuli causes upregulation of Trx1. Trx1 antagonizes hypertrophy at baseline and in response to hypertrophic stimuli. Trx1 inhibits cardiac hypertrophy in part through reduction of oxidized (S-thiolated) signaling molecules.

 
Using specific inhibition of Trx by dominant negative and antisense approaches, we have recently shown that endogenous Trx1 plays a critical role in regulating oxidative stress and inhibiting cardiac hypertrophy both at baseline and in response to pressure overload [18]. Expression of endogenous Trx1 is upregulated in response to pressure overload, while exogenous overexpression of wild-type Trx1 reduced levels of hypertrophy and oxidative stress in response to pressure overload [18]. Because the antihypertrophic effect of Trx1 is active both at baseline and in response to stress, thioredoxin belongs to both the first and the second groups of negative regulators of cardiac hypertrophy. It has been shown that Trx1 attenuates adriamycin-induced cardiotoxicity [58], ischemia/reperfusion injury [59] and reperfusion-induced arrhythmias [60], suggesting that Trx1 has additional cell protective effects in the heart when it is overexpressed. Alternatively, the cell protective effects of Trx might be primarily mediated by Trx2, an isoform localized at mitochondria [61]. In some cell types, such as cancer cells, Trx1 is secreted and works as a growth factor [62,63]. In vascular smooth muscle cells, inhibition of Trx activity by vitamin D3-upregulated protein-1 (VDUP1) prevents PDGF-induced proliferation [64]. At present, the cellular mechanism explaining the cell type-specific action of Trx1 is unknown.

Antihypertrophic effects of Trx1 are in part mediated through its effects upon reactive oxygen species. Cardiac hypertrophy caused by overexpression of dominant-negative Trx1 was inhibited by treatment with the antioxidant 2-mercaptopropyonyl glycine [18]. It has been shown that S-thiolation of Ras is enhanced in the presence of dominant-negative Trx1 [18]. Because a number of signaling molecules, including receptors, G-proteins, protein kinases, phosphatases and transcription factors are regulated by S-thiolation, identifying the molecules, whose cysteine-targeted oxidation is critically regulated by Trx1 in cardiac myocytes, may provide us with important clues to elucidate the mechanism of cardiac hypertrophy by oxidative stress.

It has been found that the protein expression of Trx1 is modified in some cardiovascular diseases [58,65,66]. The activity of endogenous Trx1 can be posttranslationally modified through interaction with other antioxidant mechanisms and oxidant species. For example, Cys72 of Trx1 undergoes glutathiolation in response to oxidative stress, which abolishes the enzymatic activity of Trx1 [67]. By contrast, nitric oxide S-nitrosylates Cys69 of Trx1, thereby stimulating the activity of Trx1 [68]. The activity of Trx1 is also subjected to regulation by the Trx1-interacting proteins such as VDUP1 [64]. Thus, cardiac hypertrophy may be affected by these mechanisms through modulation of Trx1.


   6. Therapeutic implications
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
 5. Trx1
 6. Therapeutic implications
References
 
Modulating the negative regulators of hypertrophy may become an important strategy for heart failure treatment in the future. Interventions to prevent downregulation of the first group of the negative regulators in response to hypertrophic stimuli may prevent development of cardiac hypertrophy, while enhancement of upregulation of the second group of the negative regulators may prevent progression of hypertrophy and/or development of heart failure or even promote regression of hypertrophy. Although some molecules, including ANF/BNP, have been already used for treatment of heart failure, expanding the list of molecules in this group seems important, because the negative feedback mechanism is generally assumed to be a fundamental mechanism for the biological system to maintain homeostasis. Enhancing these naturally preferred mechanisms may have advantages over artificially designed strategies to prevent cardiac hypertrophy.

Accumulating evidence suggests that some forms of hypertrophy are purely compensatory, while others lead to congestive heart failure [69]. Although the signaling mechanisms mediating physiological or pathological hypertrophy are not fully understood, it has been proposed that either qualitative or quantitative differences in activation or inactivation of some signaling molecules may explain the differences in phenotype and prognosis among various forms of hypertrophy [69]. In this regard, it is possible that negative feedback regulation of cardiac hypertrophy could be also either salutary or detrimental. For example, Trx1 not only reduces hypertrophy in response to pressure overload but also promotes cell survival and reduces the size of myocardial infarction in response to ischemia/reperfusion in mice [18,59]. Thus, it is speculated that negative regulation of hypertrophy by Trx1 may be salutary for the heart. By contrast, ICER not only inhibits cardiac hypertrophy but also stimulates apoptosis in response to β-AR stimulation in cardiac myocytes [44]. In this case, inhibition of hypertrophy by ICER may rather promote decompensation through enhancement of apoptosis, while suppression of ICER may selectively promote compensatory hypertrophy, although this hypothesis needs to be tested in vivo. These examples suggest that the effect of a negative regulator of hypertrophy upon other cellular events, especially cell death/survival, needs to be evaluated carefully, when these molecules are considered as a modality to modulate cardiac hypertrophy in patients.

Some of the negative regulators of cardiac hypertrophy have a wide variety of functions not limited to the heart but also in other organs and other disease states, which may lead to attenuation or even reversal of the antihypertrophic effects upon hearts. For example, PPAR agonists have important functions in the lipid metabolism and glucose homeostasis. Agonists of PPAR{alpha} inhibit cardiac myocyte hypertrophy [70,71]. PPAR{alpha} is downregulated during cardiac hypertrophy. Thus, PPAR{alpha} may belong to the first group of negative regulators. Interestingly, however, cardiac-restricted transgenic overexpression of PPAR{alpha} in mice leads to repression of the genes involved in glucose transport and utilization, which induces a diabetic state and secondarily stimulates LVH [72]. This provides an example showing that the sword to inhibit hypertrophy may have two edges, with the unwanted one sometimes prevailing.

Given the numerous stimuli and pathways leading to cardiac hypertrophy, we can easily speculate that we may not identify a single "magic bullet" among the negative regulators of LVH, which would enable us to prevent all adverse effects of the disease. Much effort has to be made in order to apply our knowledge to treatment of LVH. An important goal for the future would be to regulate the right signaling pathway in response to a given hypertrophic stimulus in a very specific manner, in terms of timing, specific cell type, and subcellular localization. Considering the rapid progress in our knowledge regarding the signaling mechanisms of hypertrophy, however, it is expected that the coming years should bring us better modalities modulating these negative regulators either independently or in combination to treat cardiac hypertrophy and heart failure.


   Acknowledgements
 
This work was in part supported by US Public Health Service Grants HL 59139, HL67724, HL67727, HL69020, by American Heart Association 9950673N, 0940123N, and 0325409T and by the Deutsche Forschungsgemeinschaft HA 2959/2-1.


   Notes
 
Time for primary review 21 days


   References
Top
 Abstract
 1. Introduction
 2. Classifications of inhibitors...
 3. GSK-3β
 4. ICER
 5. Trx1
 6. Therapeutic implications
 References
 

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