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  • Review Article
  • Published:

Kinases as therapeutic targets for heart failure

Key Points

  • Despite the fact that multiple drug classes are used to treat heart failure patients, new cases of heart failure are growing at over 10% per year. The risk of death is 5–10% annually in patients with mild symptoms of heart failure, and increases to 30–40% annually in patients with advanced heart failure. Therefore, there is an unmet medical need for novel therapies to treat heart failure.

  • Kinases catalyze reversible phosphorylation reactions that are responsible for the direct or indirect control of most signalling pathways in cardiac cells. Because of their central role in cellular signalling, these enzymes are attractive therapeutic targets.

  • Protein kinase C (PKC), the mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) have, in particular, been implicated in various functional responses in cardiac cells, including hypertrophy, cell survival and cardiac protection, cell (organ) size, response to stress, calcium regulation and contraction.

  • PKC, MAPK and PI3K each represent families of closely related proteins that might have selective roles in the above responses. In some cases, inhibition of selected isoforms would be beneficial to cardiac function and organ survival (for example, PKC-α, -β and -δ, PI3Kγ, p38-MAPK and JNK), whereas in other cases inhibition of other isoforms could be detrimental while their activation could be beneficial (for example, PKC-ε, PI3K-α, MAPK1/3).

  • Inhibitors of the PKC, MAPK, and PI3K families have been useful tools in understanding signal transduction pathways and in defining the function of these kinases in the onset and progression of heart failure. Inhibitors of protein kinases are being investigated in the clinic for the treatment of cancer, inflammation and diabetic complications. As kinase pathways involved in cardiac function and regulation are further elucidated, and as selective isoform inhibitors of the kinases discussed in this review are developed, it is conceivable that new therapeutics targeting specific kinases (by activating beneficial pathways and/or by inhibiting detrimental pathways) might be used in conjunction with existing heart failure therapies.

Abstract

Cardiac cells respond to external stimuli by activating signal-transduction cascades involving protein and lipid kinases. These enzymes are attractive therapeutic targets as they are responsible for the direct or indirect control of most signalling pathways in cells. Existing therapies for heart failure are directed against the renin-angiotensin system and the β-adrenoceptor, and prevent the initiation of signalling cascades. However, as molecular signalling events in the progression of heart failure are elucidated, new downstream signalling targets have emerged as candidates for therapeutic intervention.

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Figure 1: Kinase inhibitors.
Figure 2: Role of PI3K in cardiac hypertrophy and contraction.
Figure 3: MAP kinase cascades.
Figure 4: Gαq-protein coupled receptor responses in cardiomyocyte function.

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Correspondence to Chris J. Vlahos.

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DATABASES

AngII

ERK1

ERK2

ET1

GSK3-b

Igf1

MAP2K1

MAP2K2

MAP2K3

MAP2K4

MAP2K6

MAP2K7

MAPK7

Mekk1

p38

PKC-α

PKC-β1

PKC-δ

PKC-ε

PKC-θ

PKC-μ

PKC-γ

PKC-η

PKC-ζ

FURTHER INFORMATION

Encyclopedia of Life Sciences

Cardiovascular disease: epidemiology

ischaemic heart disease

Glossary

CONGESTIVE HEART FAILURE

Insufficiency of the heart to act as a pump, thereby failing to maintain blood circulation. Symptoms include fatigue (limiting exercise tolerance), fluid retention (leading to pulmonary and peripheral edema) and difficulty in breathing.

HYPERTROPHY

Increase in size, but not in number, of cardiomyocytes leading to an increase in heart mass. Concentric hypertrophy is the thickening of the walls of the heart with apparent diminution of chamber capacity. Eccentric hypertrophy is the thickening of the walls of the heart with chamber dilation.

KINASE

Enzyme that catalyzes the reversible addition of a phosphate group to proteins, lipids and carbohydrates.

ISOFORM

Multiple forms of the same class of protein possessing similar functional characteristics but that differ slightly in amino acid sequence either by alternative splicing at the transcript level of the same gene or encoding by different genes.

β-ADRENOCEPTORS

Catecholamine-responsive, seven-transmembrane spanning, G-protein-coupled receptors. Three cardiac isoforms have been identified: β1 predominates in cardiomyocytes and couples only to Gs, whereas β2 couples to both Gs and Gi regulatory proteins. Coupling to Gs stimulates adenylate cyclase formation of cAMP. β3, in contrast to β1 and β2, inhibits contractile function.

L-TYPE CALCIUM CHANNEL

A dihydropyridine-sensitive calcium channel that serves as the major point of entry for calcium into the cardiomyocyte.

PRESSURE-OVERLOAD

Animal model of cardiac hypertrophy induced by aortic constriction.

MYOCARDIAL INFARCTION

An area of necrosis in the heart resulting from an interruption of blood supply (ischaemia).

RENIN-ANGIOTENSIN SYSTEM

The clinical symptoms of CHF stimulate the release of renin from the kidneys leading to the conversion of circulating angiotensinogen to inactive angiotensin-I (AngI) which, in turn, is converted to the active AngII by angiotensin-converting enzyme (ACE), located ubiquitously along vascular walls. AngII stimulates adrenal aldosterone secretion resulting in sodium accumulation and arteriolar constriction, thereby increasing peripheral vascular resistance. AngII can also stimulate cardiac hypertrophy. Current heart failure therapies include inhibitors of ACE and angiotensin receptor blockers.

ISCHAEMIA

Reduced blood flow due to arterial occlusion.

APOPTOSIS

Programmed cell death, characterized by death receptor ligand or mitochondria-elicited activation of caspase proteases, which leads to nuclear condensation, DNA fragmentation and clearance of the dead cell by surrounding tissue.

G-PROTEIN COUPLED RECEPTOR

(GPCR). Seven-transmembrane spanning receptors that couple to G-proteins. G-proteins are αβg heterotrimers. Ligand stimulation releases GDP bound to the α subunit, enabling a conformational change with GTP binding, and dissociation of βγ dimers. Both the α and βγ subunits stimulate downstream signaling events. α subunits have been categorized as Gαs, Gαι, and Gαq.

HYPOXIA

Deficient tissue oxygenation.

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Vlahos, C., McDowell, S. & Clerk, A. Kinases as therapeutic targets for heart failure. Nat Rev Drug Discov 2, 99–113 (2003). https://doi.org/10.1038/nrd1009

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