title: Interference with ERK(Thr188) phosphorylation impairs pathological but not physiological cardiac hypertrophy.
abstract: 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 ERK(Thr188) autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK(Thr188) phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK(Thr188) 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 ERK(Thr188) 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 ERK(Thr188) phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK(Thr188) 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 ERK(Thr188) phosphorylation (i) inhibits pathological hypertrophy and (ii) does not impair antiapoptotic ERK1/2 signaling and because ERK(Thr188) phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK(Thr188) phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Ruppert
authors.forename: Katharina
authors.initials: K
authors.lastname: Deiss
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herrmann
authors.forename: Marie
authors.initials: M
authors.lastname: Vidal
authors.forename: Mehmet
authors.initials: M
authors.lastname: Oezkur
authors.forename: Armin
authors.initials: A
authors.lastname: Gorski
authors.forename: Frank
authors.initials: F
authors.lastname: Weidemann
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Kristina
authors.initials: K
authors.lastname: Lorenz
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D006332:Cardiomegaly / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D002470:Cell Survival; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D005260:Female; D006321:Heart / Q000254:growth & development / Q000503:physiopathology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010769:Phosphothreonine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3