ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a "good" player to be stimulated or a "bad" actor to be mitigated, depending on the pathophysiological context.

Keywords: ERK pathway; RASopathies; adaptive and maladaptive hypertrophy; anthracycline-induced cardiotoxicity; hypertrophic cardiomyopathy; target therapies.

Figure 1

Simplified view of cardiac hypertrophy. The normal heart develops left ventricular remodeling in response to physiological (exercise and pregnancy) and pathological (pressure or volume overload, myocardial infarction, hypertension, drug toxicity, and congenital heart defects) stimuli. In the physiological hypertrophy, cardiomyocytes increase in length and width. In the concentric hypertrophy, cardiomyocytes mostly increase in width compared with length. In the eccentric hypertrophy, cardiomyocytes mostly grow in length compared with width, leading to dilated cardiomyopathy. Except for physiological hypertrophy, hypertrophic remodeling can progress to contractile dysfunction and heart failure.

Figure 2

Schematic view of the ERK pathway in response to growth factors, hormones, and mechanical stress. The prototypical activation of ERK cascade is initiated at the plasmamembrane by receptor tyrosine kinases (RTKs) in response to growth factors. Activated RTKs promote RAS stimulation through recruitment of SOS exchange factor. RAS facilitates the activation of MEK-ERK cascade through serial phosphorylation. Once activated, ERK translocates to the nucleus and phosphorylates transcription factors, modulating the transcription of hundreds of genes. In cardiac myocytes under stress (aortic stenosis and hypertension), ERK is activated in response to G protein-coupled receptors (GPCRs), and/or “stretch-sensitive” sensors, such as membrane bound integrins, and the sarcomere. The activation of ERK cascade is regulated by scaffold proteins (KSR, Shoc2, Erbin, β-arrestin, IQGAP, Melusin, FHL1, and ANKRD1), which bind components of the RAF-MEK-ERK module, facilitating their functional interaction and subcellular localization. Scaffolds also link the ERK activation to specific upstream signal and affect the duration of the signal.