Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy.

Authors:
Ersilia Cipolletta
Ersilia Cipolletta
Department of Clinical Medicine
Italy
Maria Rosaria Rusciano
Maria Rosaria Rusciano
University of Naples Federico II
Italy
Angela Serena Maione
Angela Serena Maione
University of Naples Federico II
Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Antonietta Franco
Antonietta Franco
Washington University School of Medicine
Italy

PLoS One 2015 25;10(6):e0130477. Epub 2015 Jun 25.

Department of Translational and Medical Sciences, Federico II University, Naples, Italy.

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.

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Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481531PMC
March 2016
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