Interference with ERKThr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERKThr188 autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERKThr188 phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERKThr188 phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2(T188A), which is dominant-negative for ERKThr188 signaling. ERK2(T188A) efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2(T188A) did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERKThr188 phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERKThr188 phosphorylation was increased 8.5 +/- 1.3-fold in high-gradient, rapidly progressing cases (>= 40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERKThr188 phosphorylation (i) inhibits pathological hypertrophy and (ii) does not impair antiapoptotic ERK1/2 signaling and because ERKThr188 phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERKThr188 phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.