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  • Review Article
  • Published:

Regulation of cardiac hypertrophy by intracellular signalling pathways

Key Points

  • This review discusses the intracellular signal-transduction pathways that control the growth of the myocardium, with a special emphasis on potential therapeutic targets for treating pathological hypertrophy and heart failure.

  • The current review addresses the different forms of adult cardiac hypertrophy and the signalling pathways that might underlie each form.

  • Signalling proteins such as mitogen-activated protein kinase (MAPK) as well as pathways such as, calcineurin–nuclear factor of activated T cells (NFAT) and insulin-like growth factor-I (IGF-I)–phosphatidylinositol 3-kinase (PI3K)–AKT/protein kinase B (PKB)–mammalian target of rapamycin (mTOR) are important mediators of cardiac hypertrophy.

  • Cyclin-dependent kinases 7 (CDK7) and CDK9 as well as kinase-regulated shuttling of class II histone deacetylases (HDACs) have been shown to regulate cardiac hypertrophy.

  • Data that is generated from genetically modified animal models in which single gene function was evaluated by gain or loss of expression approaches have shed light on the signalling networks that mediate cardiac hypertrophy.

  • Transcriptional mechanisms whereby intracellular signalling pathways communicate with the nucleus to regulate growth-dependent gene expression are also discussed.

Abstract

The mammalian heart is a dynamic organ that can grow and change to accommodate alterations in its workload. During development and in response to physiological stimuli or pathological insults, the heart undergoes hypertrophic enlargement, which is characterized by an increase in the size of individual cardiac myocytes. Recent findings in genetically modified animal models implicate important intermediate signal-transduction pathways in the coordination of heart growth following physiological and pathological stimulation.

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Figure 1: Integrated schematic of the more extensively characterized intracellular signal-transduction pathways that coordinate the cardiac hypertrophic response.
Figure 2: Different phenotypes of cardiac hypertrophy.
Figure 3: Calcineurin–NFAT signalling in cardiac myocytes.

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Acknowledgements

J.H. was funded, in part, by a fellowship grant from the Deutsche Forschungsgemeinschaft. J.D.M was supported by grants from the National Institutes of Health, the American Heart Association and the Fondation Leducq.

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Glossary

Oedema

Interstitial accumulation of fluid (for example, in the lung or at the ankle) that occurs in heart failure. Oedema is a result of increased venous hydrostatic pressure that is due to reduced cardiac function with impaired venous blood return to the heart.

Myocarditis

Inflammatory disease of the heart that is usually caused by viral infection or autoimmune processes. In some cases, myocarditis leads to irreversible cardiac dilation and heart failure.

Arrhythmia

Abnormally fast, slow, or non-rhythmic heart rate that is due to conduction defects, extraneous sites of excitatory action potentials or alterations in ionic currents at the level of the myocyte. Arrhythmia can lead to (sudden) death.

Eccentric hypertrophy

Uniform cardiac growth response that is associated with a matched increase in ventricular walls, septum and chamber dimensions. Cardiac myocytes grow in width and in length, although length increases are more prominent.

Sarcomeres

Repetitive units of overlapping myosin-containing thick filaments and actin-containing thin filaments that generate force when they slide over one another.

Concentric hypertrophy

Cardiac growth that is associated with thickening of the ventricular walls and septum, with no increase, or a net decrease, in chamber volume. Cardiac myocytes typically grow more in width than in length.

Compensated hypertrophy

Enhanced myocardial growth with preserved or even enhanced cardiac function. Compensated hypertrophy is sometimes followed by a state of decompensated hypertrophy with reduced cardiac performance and heart failure.

AKAP79

(A-kinase anchoring protein-79). A kinase anchoring protein that binds protein kinase A and calcineurin, and functions as a potent non-competitive inhibitor of calcineurin when overexpressed.

Cabin-1

Also known as cain, cabin-1 is a 240-kDa protein with a wide tissue distribution (high expression in brain, lung and liver) that binds to calcineurin within a 38-amino-acid domain near the cabin-1 C terminus and functions as a potent non-competitive inhibitor of calcineurin when overexpressed.

Aortic banding

A surgical procedure in which a ligature of defined constriction is placed around the aorta. In the mouse, this is typically performed in the thoracic cavity at the level of the ascending or transverse aorta, resulting in increased cardiac afterload, and hypertrophy as a secondary consequence.

Angiotensin II or isoproterenol infusion

Cardiovascular acting agonists that induce a specific effect on the heart to either promote hypertrophy or cardiomyopathy over short periods of infusion (14–28 days).

eIF2B

A GEF (guanine nucleotide-exchange factor) that, together with its substrate eIF2, regulates the translation-initiation phase of protein synthesis.

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Heineke, J., Molkentin, J. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7, 589–600 (2006). https://doi.org/10.1038/nrm1983

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