Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy

Abstract

Cardiac hypertrophy results from increased mechanical load on the heart and through the action of neurohumoral mediators. ERK1/2 are known to be activated in response to almost every stress- and agonist-induced hypertrophic stimulus examined to date, suggesting the straightforward hypothesis that these kinases are required for promoting the cardiac growth response. However, recent data from genetically modified mouse models suggest a more complicated picture. For example, inducible expression of dual-specificity phosphatase 6, an ERK1/2-inactivating phosphatase, eliminated ERK1/2 phosphorylation in transgenic mice, but it did not diminish the hypertrophic response to pressure overload. Similarly, Erk1-/- and Erk2+/- mice showed no reduction in stimulus-induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload. Thus, ERK1/2 signaling is not to be absolutely necessary for mediating cardiac hypertrophy, although it does appear to provide critical protective effects/signals during stress-stimulation.

Figure 1

The MAPK signaling cascades are composed of three to five levels of kinases that constitute a phosphorylation-based amplification network. They are generally sub-classified into three main branches, consisting of p38 kinases, c-Jun N-terminal kinases (JNKs), and ERK1/2. However, additional kinases in this cascade include ERK5, which is activated by MEK5.

Figure 2

Working model for ERK activation. Baseline levels of phospho-ERK oscillate at baseline. A stimulus activating the ERK pathway increase the level of activated ERK. In contrast, mice with overexpression of activated MEK1 have sustained increased activation, and mice with overexpression of DUSP6 have very low baseline and post-stimulus levels. Mice with deletion of DUSP6 appear to have increased baseline activation, but unchanged post stimulus levels.