Targeting the CaMKII/ERK interaction in the heart prevents cardiac hypertrophy

Ersilia Cipolletta, Maria Rosaria Rusciano, Angela Serena Maione, Gaetano Santulli, Daniela Sorriento, Carmine Del Giudice, Michele Ciccarelli, Antonietta Franco, Catherine Crola, Pietro Campiglia, Marina Sala, Isabel Gomez-Monterrey, Nicola De Luca, Bruno Trimarco, Guido Iaccarino, Maddalena Illario

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Aims: Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. Methods and Results: In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. Conclusion: These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.

Original languageEnglish (US)
Article numbere0130477
JournalPloS one
Volume10
Issue number6
DOIs
StatePublished - Jun 25 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Cipolletta, E., Rusciano, M. R., Maione, A. S., Santulli, G., Sorriento, D., Del Giudice, C., Ciccarelli, M., Franco, A., Crola, C., Campiglia, P., Sala, M., Gomez-Monterrey, I., De Luca, N., Trimarco, B., Iaccarino, G., & Illario, M. (2015). Targeting the CaMKII/ERK interaction in the heart prevents cardiac hypertrophy. PloS one, 10(6), [e0130477]. https://doi.org/10.1371/journal.pone.0130477