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Cardiovascular Research 2004 63(3):367-372; doi:10.1016/j.cardiores.2004.06.012
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Copyright © 2004, European Society of Cardiology

Synchronization and integration of multiple hypertrophic pathways in the heart

Klaus-Dieter Schlüter*,a and Kai C Wollertb

aPhysiologisches Institut, Universität Giessen, Aulweg 129, 35392 Giessen, Germany
bAbteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany

* Corresponding author. Tel.: +49-641-99-47-212; fax: +49-641-99-47-219. Email address: klaus-dieter.schlueter{at}physiologie.med.uni-giessen.de

Received 9 June 2004; accepted 16 June 2004

Nine years ago, Cardiovascular Research (vol. 30(4), 1995) published a Spotlight Issue on signal transduction summarizing important cellular signaling events in cardiovascular cells. At that time, a main focus of research was centered on intracellular cascades modifying cellular responses in multiple cardiovascular cells, including vascular smooth muscle cells, cardiac fibroblasts, and cardiomyocytes. The present Spotlight Issue is intended to give the readership of Cardiovascular Research an update on the aforementioned signaling cascades involved in myocardial hypertrophy and to point out what has become increasingly evident during the last decade: multiple hypertrophic pathways work together in a complex scenario by integration and synchronization of a multitude of signals generated by distinct mechanisms. This editorial briefly introduces the topics covered in this Spotlight Issue.


   1. Definitions
Top
 1. Definitions
2. Example 1: neurohumoral...
 3. Example 2: the...
 4. Example 3: cross-talk...
 5. Outlook
 References
 
Epidemiological evidence from the Framingham study identifies myocardial hypertrophy that occurs in pathological conditions of chronically increased workload (e.g. hypertension, valvular heart disease, myocardial infarction) as a risk factor for the development of heart failure [1]. Cardiovascular disease and heart failure in particular are key factors contributing to morbidity and mortality in the industrialized world. Intensive investigation has therefore focussed on the molecular mechanisms controlling myocardial hypertrophy. The term myocardial hypertrophy describes several aspects of cardiac growth. As suggested by Dorn et al. [2], the term hypertrophy in its pure sense should be used to describe the presence of enlarged cardiomyocytes. In general, hypertrophy characterizes cell growth in the absence of cell division and is used to make a distinction between hyperplastic and hypertrophic growth. Hypertrophy is a specific form of growth occurring in terminally differentiated cells (e.g. cardiomyocytes). After birth, increases in cardiac mass are largely due to hypertrophic growth. Myocardial hypertrophy is controlled by prohypertrophic mediators (growth factors and mechanical stress) and inhibitory factors (Fig. 1). It is caused by a predominance of prohypertrophic mediators or a reduced impact of inhibitory factors. As reviewed in this Spotlight Issue, pro- and anti-hypertrophic mediators interact at multiple levels to control the hypertrophic response.


Figure 1
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  		Fig. 1 Three levels of induction of myocardial hypertrophy. (A) Reduction in the rate of protein degradation increases protein mass and cell size [examples are thyroid hormone [60] and neuropeptide Y (NPY, Ref. [10])]. (B) Reduction of anti-hypertrophic input leads to a dominance of pro-hypertrophic factors [examples are β-adrenoceptor (β-AR, Ref. [28]) and soluble guanylyl cyclase (sGC, Ref. [51])]. (C) Increased input of pro-hypertrophic factors (examples are {alpha}-adrenoceptor stimulation ({alpha}-AR, Ref. [5]) and angiotensin II [8]).

 
Hypertrophic growth of the heart does not always lead to heart failure but may help the heart to adapt to increases in workload. An example of such physiological adaptation of the myocardium through hypertrophic growth is the increase of left ventricular mass after birth. Another example is the adaptation of heart size to physical activity. Thus, in certain situations, myocardial hypertrophy appears to be an adaptive process leading to preserved contractile function. This apparently positive aspect of hypertrophy, however, is not in line with the epidemiological evidence provided, for example, by the Framingham study that indicates that an increased heart size in pathological conditions is a risk factor for cardiac mortality. Recently, it has emerged that it is not cardiac hypertrophy per se (i.e. increased cell size) that determines progression to heart failure, but that certain signaling pathways and gene expression patterns that are activated in pathological conditions are maladaptive. This important difference between adaptive and maladaptive hypertrophy is discussed in greater detail by Selvetella et al. [3] in this Spotlight Issue.

Much work has been performed during the last decades to identify factors that modulate the balance between protein synthesis and degradation in myocardial cells. Those that have been identified in adult heart cells are summarized in Table 1. In vivo, cardiomyocytes are exposed to multiple agonists in their direct environment, including hormones, neurotransmitters, and cytokines. The relationship between these agonists and the synchronization and integration of intracellular signals generated by them defines the overall influence on growth regulation. Interactions between these agonists can be described as cross-talk or network pathways. As outlined by Dzimiri [21], the concept of cross-talk originated in the early 1980s when it was found that {alpha}-adrenoceptors can inhibit the response to β-adrenoceptors at the post-receptor level. Therefore, the term cross-talk is used to describe inhibitory interactions between distinct signaling pathways. However, signaling pathways can also interact in a more complex way, including positive interaction in addition to inhibitory effects, forming networks. In that case, signaling pathways activated by one factor are also positively modulated by other factors: such interactions are referred to as networks.


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  		Table 1 Hypertrophic growth stimuli in adult ventricular cardiomyocytes

 

   2. Example 1: neurohumoral factors
Top
 1. Definitions
 2. Example 1: neurohumoral...
3. Example 2: the...
 4. Example 3: cross-talk...
 5. Outlook
 References
 
Mechanical factors contribute directly to the regulation of hypertrophic growth. Integrins, for example, have been identified as important cellular mechanoreceptors. The impact of integrins on the growth regulation of the heart is outlined in this Spotlight Issue by Robert Ross [22]. In addition to mechanical factors, neurohumoral factors and cytokines are intricately involved in the hypertrophic response. Mechanical stress is often accompanied by the release of cytokines, e.g. fibroblast growth factors, as described in greater detail by Kaye et al. [4]. One of the most impressive experiments demonstrating that neurohumoral factors contribute to the growth response of the heart to pressure overload comes from the group of Rockman et al. [23]. They observed that aortic banding of dopamine β-hydroxylase-deficient mice, which are not able to synthesize norepinephrine, results in a blunted hypertrophic response as compared to wild-type mice [23]. In this issue, Barki-Harrington et al. review the extensive network between different adrenoceptors that has emerged from transgenic animal studies [24].

Norepinephrine is released from transmural nerve endings leading to an activation of cardiac β- and {alpha}-adrenoceptors. Classical experiments using pharmacological agonists that selectively activate either {alpha}- or β-adrenoceptors have revealed that the {alpha}1A-adrenoceptor promotes acceleration of protein synthesis and hypertrophy most efficiently. Norepinephrine activates Gq-coupled {alpha}-adrenoceptors and G{alpha}s-coupled β-adrenoceptors. While stimulation of Gq leads to an increase in protein synthesis via activation of protein kinase C (PKC), PI 3-kinase, and subsequently p70s6k [12,25,26], stimulation of β1-adrenoceptors leads to an activation of the adenylyl cyclase/protein kinase A cascade and a cAMP-independent increase in protein synthesis [6]. The participation of the aforementioned intracellular signaling pathways in the regulation of protein synthesis is discussed in greater detail by Proud [27]. It is generally accepted that the initial step in the {alpha}-adrenoceptor-dependent increase in protein synthesis is an activation of PKC. Norepinephrine binds to and activates several adrenoceptor subtypes and the overall effect on protein synthesis is lower than that evoked by the sole activation of {alpha}1A-adrenoceptors [28]. Signaling cross-talk is responsible for this outcome. First, β-adrenoceptors cause a cAMP-dependent inhibition of PKC activation [28], and second, {alpha}-adrenoceptors cause a Gi-dependent and PKC-dependent inhibition of adenylyl cyclase activation [29]. Consequently, simultaneous activation of both receptors results in less hypertrophic growth response than selective stimulation of {alpha}-adrenoceptors (see Fig. 2). This cross-talk is differentially regulated under conditions of chronic catecholamine excess (e.g. in chronic heart failure), which desensitizes the β-adrenoceptor system and reduces its inhibitory impact on the regulation of cardiac mass. Novel β-adrenoceptor blockers with a more complex pharmacological profile may be used to modify the hypertrophic response to norepinephrine and may offer new strategies for pharmacological intervention [30]. This example illustrates how knowledge of post-receptor interactions may improve our understanding of pharmacological interventions in cardiac hypertrophy and failure. β-Adrenoceptors are also involved in other types of cross-talk as outlined in this issue by Pepe et al. for opioid peptide receptors [31].


Figure 2
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  		Fig. 2 Dependence of the protein kinase C (PKC)/phosphatidylinositol 3-kinase (PI 3K)/Akt kinase (Akt) pathway activated by {alpha}-adrenoceptor stimulation on co-activation of β1-adrenoceptors (β1) or CRL receptors (CRLR) by norepinephrine or adrenomedullin, respectively. The inhibitory effect of these pathways can be reduced by neuropeptide Y (NPY), which can be co-released from transmural nerve endings together with norepinephrine. NPY acts via stimulation of specific receptors (Y-R).

 

   3. Example 2: the renin–angiotensin system
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 1. Definitions
 2. Example 1: neurohumoral...
 3. Example 2: the...
4. Example 3: cross-talk...
 5. Outlook
 References
 
The renin–angiotensin–aldosterone system (RAAS) is one of the most important hormonal systems involved in the development of cardiac hypertrophy, although it appears to have a relatively low direct impact on protein synthesis in adult ventricular cardiomyocytes [8]. There is evidence that the components of the renin–angiotensin system are not only of systemic relevance but are also active locally in the ventricle [32]. It has been speculated that changes in local expression of the RAAS may contribute to the development and progression of heart failure [33,34]. Angiotensin II activates two distinct receptors, the AT1 and AT2 receptor [35]. Inhibition of AT1 receptors in spontaneously hypertensive rats is sufficient to reduce cardiac mass and improve cardiac function [36]. It is less clear, however, whether angiotensin II contributes directly or indirectly to the increase in cardiac mass. For example, AT1 receptor knock-out mice still respond to pressure overload with hypertrophy [37,38]. Therefore, in contrast to the catecholamines, activation of the renin–angiotensin system seems not to be required for pressure-induced hypertrophic growth.

The ability of angiotensin II to activate two distinct populations of receptors has led to studies investigating the interaction between these receptors. An inhibitory effect of AT2 receptor stimulation on AT1 receptor-dependent processes has been shown (reviewed in Ref. [39]). Furthermore, there is evidence for cross-talk between the AT1 receptor and adrenoceptors. In neonatal cardiomyocytes, angiotensin II causes a decrease in {alpha}1A-adrenoceptor expression [40]. In addition, PKC activation by angiotensin II is also sufficient to decrease β-adrenoceptor responsiveness in the heart [41]. Finally, angiotensin II downregulates the expression of bradykinin receptors, which inhibit protein synthesis (for details, see below).

Transactivation of different receptor systems is another way in which angiotensin II is linked to growth regulation of cardiac cells (Fig. 3). A prominent example is the EGF receptor [42]. Angiotensin II transactivates the EGF receptor via activation of metalloprotease 12, which initiates the production of heparin-binding EGF [42]. Subsequently, the EGF receptor kinase is activated and initiates p42/p44 MAP-kinase activation [43,44]. Another example in which other growth stimuli contribute to the angiotensin II signal is FGF. In the absence of FGF, hypertension evoked by angiotensin does not induce cardiac hypertrophy [45]. Again, p42/p44 MAP kinase activation is a key step. Release of the prohypertrophic factor endothelin-1 from cardiomyocytes in response to angiotensin II stimulation is another example for transactivation by angiotensin II [46].


Figure 3
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  		Fig. 3 Summary of effects of distinct anti-hypertrophic pathways and their effect on peripheral resistance in comparison to factors with pro-hypertrophic properties.

 
Angiotensin II strongly induces the expression of cytokines, indicating that there is a link between the RAAS system and cytokine expression in the heart. Two articles in this Spotlight Issue review our present knowledge about the interaction of these pathways [47,48]. One of them focuses on TGF-β and the other on TNF-{alpha}. Both cytokines have been proposed to play a crucial role in the transition from hypertrophy to heart failure.


   4. Example 3: cross-talk between hypertrophic and vasodilatory factors
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 1. Definitions
 2. Example 1: neurohumoral...
 3. Example 2: the...
 4. Example 3: cross-talk...
5. Outlook
 References
 
As outlined above, final heart (cell) size is the product of various stimuli that either act as pro- or anti-growth factors. Among those factors with anti-growth properties are the natriuretic peptides, which act via stimulation of receptor guanylyl cyclases [49]. The interplay between the sympathetic nervous system and natriuretic peptides is worked out in greater detail by Luchner and Schunkert [50]. Bradykinin, which induces nitric oxide (NO) release from adjacent endothelial cells, is also a negative regulator of hypertrophy [51] independent of its hemodynamic effects. A direct inhibitory effect of NO on cardiomyocyte hypertrophy response was also demonstrated in an experimental model in which NO generation was blunted by NO synthase inhibitors like L-NAME [52]. Voltage-dependent L-type calcium channels participate in the hypertrophic response evoked by IGF-I and IGF-II [14]. Studies in spontaneously hypertensive rats suggest a coupling of these channels to calcium-dependent activation of calcineurin [53]. A specific interaction between NO and the L-type calcium channel/calcineurin pathway is discussed in greater detail in the review by Fiedler and Wollert in this Spotlight Issue [54].

Finally, adrenomedullin should be mentioned in this context as it is a potent vasodilatory peptide that is expressed and secreted by cardiomyocytes. Angiotensin II, endothelin-1, isoproterenol, and mechanical stress due to pressure overload appear to be involved in the regulation of its expression in the myocardium [55,56]. Adrenomedullin acts by stimulation of calcitonin receptor-like receptors (CRLR) and stimulation of adenylyl cyclase [57]. In this respect, adrenomedullin mimics the anti-hypertrophic effects of β-adrenoceptor stimulation (see Fig. 2). A direct anti-hypertrophic effect was demonstrated in adrenomedullin-deficient mice that exhibit accelerated cardiac hypertrophy induced by angiotensin II as compared to wild-type mice [58]. Conversely, chronic administration of adrenomedullin attenuates the transition from left ventricular hypertrophy to heart failure in rats [59]. Such cross-talk might be used in the future to develop treatment protocols for myocardial hypertrophy that take into account that all these factors have not only hemodynamic but also direct cardiac effects (Fig. 4).


Figure 4
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  		Fig. 4 Complex networks to which angiotensin II contributes via activation of AT1 receptors. The scheme includes transactivation of EGF receptors (HB-EGFR) via the metalloprotease ADAM12 (ADAM), transactivation of FGF receptors (bFGF), and induction of TGF-β that induces coupling of β2-adrenoceptors to protein synthesis. Angiotensin II activates TGF-β expression via stimulation of NADPH oxidase (NADPH-Ox.) and stress-activated MAP kinase (p38 MAPK).

 

   5. Outlook
Top
 1. Definitions
 2. Example 1: neurohumoral...
 3. Example 2: the...
 4. Example 3: cross-talk...
 5. Outlook
References
 
Cross-talk, e.g. between vasodilators with direct antihypertrophic properties and prohypertrophic factors, is an important part of the basal regulation of cardiac protein turnover, size, and gene expression patterns. Networks between pro-hypertrophic pathways are able to multiply hypertrophic signals, thereby increasing efficiency and defining the phenotype. This Spotlight Issue provides an update of our present understanding of the interaction of multiple pathways contributing to hypertrophy.


   References
Top
 1. Definitions
 2. Example 1: neurohumoral...
 3. Example 2: the...
 4. Example 3: cross-talk...
 5. Outlook
 References
 

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