title: Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.affiliation: Department of Translational and Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rusciano
authors.affiliation: Department of Translational and Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Angela Serena
authors.initials: AS
authors.lastname: Maione
authors.affiliation: Columbia University Medical Center, College of Physicians & Surgeons, New York Presbyterian Hospital-Manhattan, New York, NY, United States of America.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Institute of Biostructure and Bioimaging (IBB) of Italian National Research Council (CNR), Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sorriento
authors.affiliation: Department of Advanced Biomedical Science, Federico II University, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Del Giudice
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
authors.affiliation: Department of Advanced Biomedical Science, Federico II University, Naples, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Franco
authors.affiliation: Department of Translational and Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Catherine
authors.initials: C
authors.lastname: Crola
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.affiliation: Department of Pharmacy, Federico II University, Naples, Italy.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.affiliation: Department of Translational and Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Luca
authors.affiliation: Department of Advanced Biomedical Science, Federico II University, Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.affiliation: Department of Translational and Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Illario
mesh_terms: D000818:Animals; D002070:Butadienes / Q000008:administration & dosage; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage; D010656:Phenylephrine / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats
chemical_list: D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D010656:Phenylephrine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048052:Mitogen-Activated Protein Kinase 3