Review
Molecular regulation of cardiac hypertrophy

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Abstract

Heart failure is one of the leading causes of mortality in the western world and encompasses a wide spectrum of cardiac pathologies. When the heart experiences extended periods of elevated workload, it undergoes hypertrophic enlargement in response to the increased demand. Cardiovascular disease, such as that caused by myocardial infarction, obesity or drug abuse promotes cardiac myocyte hypertrophy and subsequent heart failure. A number of signalling modulators in the vasculature milieu are known to regulate heart mass including those that influence gene expression, apoptosis, cytokine release and growth factor signalling. Recent evidence using genetic and cellular models of cardiac hypertrophy suggests that pathological hypertrophy can be prevented or reversed and has promoted an enormous drive in drug discovery research aiming to identify novel and specific regulators of hypertrophy. In this review we describe the molecular characteristics of cardiac hypertrophy such as the aberrant re-expression of the fetal gene program. We discuss the various molecular pathways responsible for the co-ordinated control of the hypertrophic program including: natriuretic peptides, the adrenergic system, adhesion and cytoskeletal proteins, IL-6 cytokine family, MEK-ERK1/2 signalling, histone acetylation, calcium-mediated modulation and the exciting recent discovery of the role of microRNAs in controlling cardiac hypertrophy. Characterisation of the signalling pathways leading to cardiac hypertrophy has led to a wealth of knowledge about this condition both physiological and pathological. The challenge will be translating this knowledge into potential pharmacological therapies for the treatment of cardiac pathologies.

Introduction

Cardiovascular disease (CVD) is one of the leading causes of death worldwide, accounting for 16.7 million deaths per annum (the World Health Organization—http://www.who.int/dietphysicalactivity/publications/facts/cvd/en/). CVD encompasses a wide spectrum of cardiac pathologies including 5.3 million people living with heart failure in the USA alone (the American Heart Association—http://www.americanheart.org/presenter.jhtml?identifier=4478). In the various forms of heart failure, excessive cardiac workload leads to an enlargement of the heart in an endeavour to manage the increased hemodynamic demand. This process, known as hypertrophy, is classified as “physiological” hypertrophy when it occurs in healthy individuals following exercise and is not associated with cardiac damage, or “pathological” hypertrophy (Fig. 1). In the case of pathological hypertrophy, although the increased heart size is initially a compensatory mechanism, sustained hypertrophy can ultimately lead to a decline in left ventricular function and thus represents an independent risk factor for heart failure (Levy, Garrison, Savage, Kannel, & Castelli, 1990). The main causes of pathological hypertrophy are hypertension, genetic polymorphisms, and loss of myocytes following ischaemic damage. Altered cardiac metabolism can also be an important component leading to hypertrophy (Rajabi, Kassiotis, Razeghi, & Taegtmeyer, 2007). Indeed, this mechanism is so prevalent in the setting of diabetes that it has led to the description of a specific syndrome of “diabetic cardiomyopathy” (Boudina & Abel, 2007).

Hypertrophic growth develops in two ways: concentric hypertrophy is caused by chronic pressure overload and leads to reduced left ventricular volume and increased wall thickness whereas eccentric hypertrophy is caused by volume overload and causes dilation and thinning of the heart wall (Wakatsuki, Schlessinger, & Elson, 2004). Mechanistically, eccentric expansion occurs by addition of sarcomeres in series causing cell elongation; concentric enlargement on the other hand is caused by addition of sarcomeres in parallel resulting in increased cell thickness. Accompanying the increase in myocyte size, there is an increase in the number of cardiac fibroblasts causing fibrosis and increased myocardial stiffness (Wakatsuki et al., 2004). This in turn leads to overload and promotes further hypertrophy and cell death, resulting in a detrimental cycle of cardiac enlargement and myocyte loss. Although hypertrophy is ultimately a detrimental process, it is nonetheless highly organized and tailored to the specific needs of the heart. Thus, pressure and volume overload lead to concentric and eccentric hypertrophy via co-ordinated activation of specific intracellular signalling pathways, ultimately altering myocyte shape in a way that is best suited to deal with the specific burden. In this review we will discuss the various molecular pathways that are responsible for the co-ordinated control of the hypertrophic program.

Section snippets

Inherited cardiomyopathy

The aetiology of cardiomyopathies can be idiopathic, immunological, toxicological or genetic but in general, a defect in normal contractile function is compensated for by hypertrophic remodelling. The two major inherited forms are hypertrophic cardiomyopathy (HCM) characterized by increased wall thickness, reduced ventricular chamber volumes and reduced diastolic function and dilated cardiomyopathy (DCM) characterized by increased chamber volume, defects in systolic function and ventricular

The fetal gene program

Following the onset of increased mechanical stress or pressure overload one of the initial molecular changes is reactivation of the so-called fetal gene program—a set of genes that are normally expressed only in the developing heart and are repressed in the adult myocardium. Activation of the fetal gene program allows co-ordinated synthesis of the proteins needed to bring about increased cardiac myocyte size and adjustment to the altered energy demands of these larger cells. Indeed,

G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) are crucial in normal cardiovascular function and in mediating the “fight or flight” response to endogenous catecholamines such as adrenaline, noradrenaline and angiotensin (see Table 1). The adrenergic receptors (ARs) are GPCRs that are highly abundant in the major arteries of the body; including the aorta, pulmonary and coronary arteries and are instrumental in orchestrating the hypertrophic response through control of contractility, vascular tone and

Interluekin-6 family of cytokines

Along with adrenergic agonists, cytokines play a major role in inducing hypertrophy. The main hypertrophic cytokines are all members of the IL-6 family and include IL-6 itself, leukaemia-inhibitory factor (LIF) and cardiotrophin-1 (CT-1). All IL-6 cytokines utilise a common receptor unit glycoprotein 130 (gp130) in combination with ligand-specific receptors and mediate their effects by the JAK/STAT, MAPK and PI(3)K pathways (Fig. 2).

In the early nineties, a search for novel mediators of

Adhesion and cytoskeletal proteins

In addition to the cytoskeletal proteins being primary end-targets of the hypertrophic response, they co-operate with adhesion molecules to sense the initial stress and transmit the hypertrophic signal inside the cells. Overload of the myocardium causes mechanical stress to the myocytes. This cellular stretch signal is transduced by integrins at focal adhesion sites on the cell surface and can result in direct rearrangement of the actin cytoskeleton. Overload also causes kinases such as the Src

Mitogen-activated protein kinase/extracellular signal receptor-regulated kinase signalling

A large body of evidence supports a role for MEK and its downstream kinases ERK1/2 (extracellular signal-regulated kinases) in the development of hypertrophy. For instance, ERK1/2 are activated in response to practically every known hypertrophic agonist (Bueno & Molkentin, 2002) and transgenic expression of constitutively active MEK1 induces concentric hypertrophy in vivo (Bueno & Molkentin, 2002; Bueno et al., 2000; Clerk, Fuller, Michael, & Sugden, 1998). Similarly, inhibition of the

Histone acetyltransferases

Histone acetyltransferases (HATs) such as p300 and CREB-binding protein (CBP) are transcriptional co-activators that cause the relaxation of chromatin structure and promote gene activation. Overexpression of CBP/p300 is sufficient to induce hypertrophy and left ventricular remodelling in transgenic mice (Gusterson, Jazrawi, Adcock, & Latchman, 2003; Yanazume, Hasegawa, et al., 2003). Interestingly, cardiac remodelling after myocardial infarction, which involves hypertrophy of the remaining

Calcium-mediated pathways towards hypertrophy

Calcium increase is another potential trigger of the translocation of pro-hypertrophic transcription factors to the nucleus. Nuclear factor of activated T cells (NFAT) was originally discovered as a transcription factor involved in the development of T cells. However it is also involved in the development of the heart, as well as skeletal muscle and the nervous system. As per many transcription factors involved in cardiac development, it is also activated during hypertrophy. In this case it is

MicroRNAs—new players in cardiac hypertrophy

MicroRNAs (miRNA) are non-coding RNAs 18–25 nucleotides in length whose function is to functionally silence-specific mRNA transcripts. There are over 400 known miRNAs in the human genome, a number which is increasing weekly (Kim, 2005). In the past 12 months, a series of papers have placed miRNAs at the centre stage in regulating the hypertrophic program. Several studies have employed a microarray approach to detect miRNAs differentially expressed during hypertrophy. Van Rooij and colleagues

Conclusion

By extension of the general observation that cardiac “hypertrophy recapitulates ontogeny”, one might anticipate that other cardiac developmental signalling pathways would be integral to hypertrophy. Indeed, emerging evidence suggests that the Wnt/β-catenin pathway is involved in hypertrophy, although, its role appears to more complicated than simply that of an on/off activator/repressor. Again, this appears to reflect its multi-faceted roles in cardiac development, during the early stages of

Acknowledgements

The authors would like to thank all of the laboratories cited within this review for their insightful and exceptional research investigating cardiac hypertrophy—we would also like to apologise to those researchers whose data we could not discuss due to space constraints. Research mentioned from the authors own laboratories was funded by the Biotechnology and Biological Sciences Research Council (PAT), the British Heart Foundation (PAT), the Gerald Kerkut Charitable Trust (PAT) and the Medical

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    SPB and SMD contributed equally to this article (surnames listed alphabetically).

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