The extracellular signal-regulated kinase (ERK) pathway: a potential therapeutic target in hypertension

Abstract

Hypertension is a risk factor for myocardial infarction, stroke, renal failure, heart failure, and peripheral vascular disease. One feature of hypertension is a hyperresponsiveness to contractile agents, and inhibition of vasoconstriction forms the basis of some of the treatments for hypertension. Hypertension is also associated with an increase in the growth and proliferation of vascular smooth muscle cells, which can lead to a thickening of the smooth muscle layer of the blood vessels and a reduction in lumen diameter. Targeting both the enhanced contractile responses, and the increased vascular smooth muscle cell growth could potentially be important pharmacological treatment of hypertension. Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase family that is involved in both vasoconstriction and vascular smooth muscle cell growth and this, therefore, makes it attractive therapeutic target for treatment of hypertension. ERK activity is raised in vascular smooth muscle cells from animal models of hypertension, and inhibition of ERK activation reduces both vascular smooth muscle cell growth and vasoconstriction. This review discusses the potential for targeting ERK activity in the treatment of hypertension.

Keywords: ERK; hypertension; smooth muscle; vasoconstriction.

Figure 1

Schematic diagram showing (A) the general signaling pathway for activation of mitogen-activated protein kinases and (B) the specific pathway for activation of extracellular signal-regulated kinase. Abbreviations: ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase.

Figure 2

Schematic diagram summarizing the potential mechanisms of extracellular signal-regulated kinase activation. Notes: Extracellular signal-regulated kinase activation can occur through stimulation of either a G protein-coupled receptor or a growth factor receptor, followed by activation of the Ras, Raf, mitogen-activated protein kinase kinase pathway. Activation of extracellular signal-regulated kinase through G protein-coupled receptors could be through direct activation of the Ras, Raf, mitogen-activated protein kinase kinase pathway, or through transactivation of a growth factor receptor, such as the epidermal growth factor receptor. This can occur through activation of a matrix metalloprotease and subsequent cleavage of a membrane-bound ligand such as heparin-binding epidermal growth factor, leading to release of the ligand and activation of the receptor. Alternatively, activation of the G protein-coupled receptor could lead to tyrosine phosphorylation of the epidermal growth factor receptor. Abbreviations: EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; HB-EGF, heparin-binding epidermal growth factor; GPCR, G protein-coupled receptor; MEK, mitogen-activated protein kinase kinase; MMP, matrix metalloprotease.

Figure 3

Schematic diagram summarizing the potential mechanisms by which extracellular signal-regulated kinase could regulate vasoconstriction. Notes: Phosphorylation of caldesmon at serine 789 is thought to inhibit the activity of this protein, thus removing its inhibitory effect on myosin adenosine triphosphatase. Alternatively, extracellular signal-regulated kinase could activate myosin light-chain kinase leading to an increase in phosphorylation of the myosin light-chains. Abbreviations: ATPase, adenosine triphosphatase; ERK, extracellular signal-regulated kinase; MLC, myosin light-chain; MLCK, myosin light-chain kinase; MLC-P, myosin light-chain phosphatase.

Figure 4

Schematic diagram summarizing the effect of extracellular signal-regulated kinase on vascular smooth muscle cell growth and proliferation through effects on gene transcription. Abbreviation: ERK, extracellular signal-regulated kinase.

Figure 5

Schematic diagram summarizing the role of extracellular signal-regulated kinase (ERK) in vascular smooth muscle and hypertension. Notes: ERK can be activated through either stimulation of G protein-coupled receptors or growth factor tyrosine kinase receptors. As well as direct activation of ERK through G protein-coupled receptors, G protein-coupled receptor-stimulated transactivation of growth factor receptors can also lead to ERK activation. ERK can also be activated through production of reactive oxygen species from both nicotinamide adenine dinucleotide phosphate oxidase and mitochondria. Activated ERK mediates vascular smooth muscle contraction and could underlie the changes in vasoconstriction in hypertension. Activated ERK also causes changes in gene transcription leading to modulation of vascular smooth muscle phenotype and increases in vascular smooth muscle cell proliferation, which could underlie the hypertrophy/hyperplasia in hypertension. Abbreviations: ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; H₂O₂, hydrogen peroxide; MEK, mitogen-activated protein kinase kinase; NAPDH, nicotinamide adenine dinucleotide phosphate; O₂, oxygen.

Figure 6

Schematic diagram showing the role of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway in the production of the isoprenoid farnesyl pyrophosphate and hence the farnesylation of Ras. Note: The site of inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway by statins is also indicated. Abbreviations: ERK, extracellular signal-regulated kinase; FPP, farnesyl pyrophosphate; HMG CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.