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  • Review Article
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Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface

Key Points

  • Sustained exposure to pathological stress stimulates the heart to hypertrophy, increasing disease and mortality risk. New therapies to blunt this process include targeting enzymes below the cell membrane that serve as strategic nodes for hypertrophy regulation.

  • Rho kinase (ROCK) is activated in cardiac hypertrophy and stimulates fibrosis and heart dysfunction. Inhibition by HA-1077 (fasudil) or Y-27632 has antihypertrophic effects and improves function in models of hypertensive–hypertrophy and infarction. Newer agents may provide better specificity.

  • Rapamycin inhibits the growth factor mTOR (mammalian target of rapamycin), which is activated by both physiological and pathological hypertrophy. Inhibition of mTOR by rapamycin reduces hypertrophy and improves function.

  • Reactive oxygen species are another target, and can be treated by antioxidants and such as resveratrol or isorhapontigenin. More potent effects, however, have been obtained by preventing uncoupling of nitric oxide synthase (NOS) by tetrahydrobiopterin (BH4).

  • Cyclic GMP and protein kinase G (PKG) are intrinsic brake systems inhibiting several hypertrophic cascades. They can be stimulated by exogenous nitric oxide donors and natriuretic peptides, although these have clinical limitations. Inhibition of phosphodiesterase 5a (PDE5a) with sildenafil may provide an attractive alternative approach.

  • Calcineurin plays a key role in pathological hypertrophy. Direct inhibition has proved less effective, but new agents that enhance calcineurin inhibitory proteins such as modulatory calcineurin-interactin protein (MCIP1; also known as DSCR1), calsarcin, and atrogin are presenting attractive alternatives.

  • Pathological stimuli result in the activation of canonical transient receptor potential channels (TRPCs) that mediate non-voltage gated influx of calcium. This stimulates calcineurin/NFAT (nuclear factor of activated T cells) and hypertrophy. A new series of 3,5-bistrifluoromethyl pyrazole inhibitors appears to target TRPC and may suppress this signal.

  • Ca2+/calmodulin-dependent protein kinase II (CaMKII) adversely modulates myocyte calcium regulation and is pro-growth and pro-arrhythmic, though targeted drug inhibition is still unavailable. Protein kinase C, in particular PKCα, also worsens calcium cycling and contractility. New bisindolylmaleimide inhibitors of PKC (Ro-32-0432, and Ro-31-8220) improve function.

  • Last, nuclear transcription regulators such as histone deacetylases (HDACs) have been targeted, and drugs such as Scriptaid and SK-7041 block HDAC and suppress pressure-overload hypertrophy.

  • These and other new agents under development pose fertile ground for quite potent approaches to block pathologic hypertrophy, perhaps opening a new chapter in the treatment of heart disease.

Abstract

Pathological stress from cardiovascular disease stimulates hypertrophy of heart cells, which increases the risk of cardiac morbidity and mortality. Recent evidence has indicated that inhibiting such hypertrophy could be beneficial, encouraging drug discovery and development efforts for agents that could achieve this goal. Most existing therapies that have antihypertrophic effects target outside–in signalling in cardiac cells, but their effectiveness seems limited, and so attention has recently turned to the potential of targeting intracellular signalling pathways. Here, we focus on new developments with small-molecule inhibitors of cardiac hypertrophy, summarizing both agents that have been in or are poised for clinical testing, and pathways that offer further promising potential therapeutic targets.

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Figure 1: Targets for small-molecule drugs that modulate hypertrophic signalling.
Figure 2: Approaches to drug discovery for cardiac hypertrophy.
Figure 3: Rho/Rho kinase (ROCK) signalling and its potential role in hypertrophy.
Figure 4: mTOR signalling and its role in cardiac hypertrophy.
Figure 5: Reactive oxygen species (ROS) signalling in hypertrophy.
Figure 6: Small-molecule regulators of the cGMP/cGK1 (PKG1) pathway.
Figure 7: Small-molecule regulators of the cardiac calcineurin axis.
Figure 8: Repression of pathological cardiac genes by class IIa histone deacetylases.

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Acknowledgements

T.A.M. thanks E. Bush for helpful discussions and L. Castonguay for assistance with the compound structures. D.A.K. is supported by NIH-PO1-HL-077180 and PO1-HL-59408 grants, and the Peter Belfer Laboratory Research Fund.

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Competing interests

T.A.M. is an employee of Gilead Sciences and owns shares of Gilead stock. He has been involved in the assessment of a number of the small-molecule inhibitors described in the Review.

D.A.K's laboratory receives funding from BioMarin, who manufacture tetrahydrobiopterin, which is discussed in this Review.

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Glossary

Sarcomere

The basic functional contractile unit of muscle. It is composed largely of the proteins actin and myosin.

Myosin

An ATPase that regulates contraction through association with actin.

Crossbridges

A mysosin–actin junction.

Actin

A primary thin filament contractile protein in the sarcomere.

Z bands

Delimit the sarcomere.

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McKinsey, T., Kass, D. Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov 6, 617–635 (2007). https://doi.org/10.1038/nrd2193

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