title: Gender-specific potential inhibitory role of Ca2+/calmodulin dependent protein kinase phosphatase (CaMKP) in pressure-overloaded mouse heart.
abstract: BACKGROUND
  Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) has been proposed as a potent regulator of multifunctional Ca2+/calmodulin-dependent protein kinases (i.e., CaMKII). The CaMKII-dependent activation of myocyte enhancer factor 2 (MEF2) disrupts interactions between MEF2-histone deacetylases (HDACs), thereby de-repressing downstream gene transcription. Whether CaMKP modulates the CaMKII- MEF2 pathway in the heart is unknown. Here, we investigated the molecular and functional consequences of left ventricular (LV) pressure overload in the mouse of both genders, and in particular we evaluated the expression levels and localization of CaMKP and its association with CaMKII-MEF2 signaling.
  
  
  RESULTS
  Five week-old B6D1/F1 mice of both genders underwent a sham-operation or thoracic aortic constriction (TAC). Thirty days later, TAC was associated with pathological LV hypertrophy characterized by systolic and diastolic dysfunction. Gene expression was assessed by real-time PCR. Fetal gene program re-expression comprised increased RNA levels of brain natriuretic peptide and alpha-skeletal actin. Mouse hearts of both genders expressed both CaMKP transcript and protein. Activation of signalling pathways was studied by Western blot in LV lysates or subcellular fractions (nuclear and cytoplasmic). TAC was associated with increased CaMKP expression in male LVs whereas it tended to be decreased in females. The DNA binding activity of MEF2 was determined by spectrophotometry. CaMKP compartmentalization differed according to gender. In male TAC mice, nuclear CaMKP was associated with inactive CaMKII resulting in less MEF2 activation. In female TAC mice, active CaMKII (phospho-CaMKII) detected in the nuclear fraction, was associated with a strong MEF2 transcription factor-binding activity.
  
  
  CONCLUSIONS
  Gender-specific CaMKP compartmentalization is associated with CaMKII-mediated MEF2 activation in pressure-overloaded hearts. Therefore, CaMKP could be considered as an important novel cellular target for the development of new therapeutic strategies for heart diseases.
authors.affiliation: Inserm, UMRS-698, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Miresta
authors.initials: M
authors.lastname: Prévilon
authors.affiliation: CEFI-Institut Claude Bernard-IFR02, Paris, France; Inserm, U823, Plateforme de Microscopie Photonique - Cytométrie en Flux, Institut Albert Bonniot Site Santé BP170-38042, Grenoble, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Pezet
authors.affiliation: Inserm, UMRS-698, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Department of Cell Physiology and Metabolism, University of Geneva, Medical School, Genève, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinet
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Inserm, UMRS-769, Université Paris-Sud, IFR141, LabEx LERMIT, Châtenay-Malabry, France; AP-HP, Hôpital Bichat, Paris, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mercadier
authors.affiliation: Inserm, UMRS-698, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rouet-Benzineb
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology*; D005260:Female; D006973:Hypertension / Q000201:enzymology*; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D012727:Sex Characteristics; D020257:Ventricular Remodeling
chemical_list: D064326:MEF2 Transcription Factors; C110531:calmodulin dependent protein kinase II phosphatase; D010749:Phosphoprotein Phosphatases