title: Calcineurin splicing variant calcineurin Aβ1 improves cardiac function after myocardial infarction without inducing hypertrophy.
abstract: BACKGROUND
  Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin Aβ (CnAβ) gene generates the CnAβ1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAβ1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown.
  
  
  RESULTS
  We generated transgenic mice overexpressing CnAβ1 in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAβ1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnAβ1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnAβ1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation.
  
  
  CONCLUSIONS
  Calcineurin Aβ1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAβ1 an attractive candidate for the development of future therapeutic approaches.
authors.affiliation: Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.forename: Takuya
authors.initials: T
authors.lastname: Narita
authors.forename: Renée
authors.initials: R
authors.lastname: Germack
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.forename: Marina M
authors.initials: MM
authors.lastname: López-Olañeta
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Gómez-Salinero
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.forename: Paul J R
authors.initials: PJ
authors.lastname: Barton
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosenthal
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: C081452:Atf4 protein, mouse; D020033:Protein Isoforms; D051701:Activating Transcription Factor 4; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse; D018995:Myosin Heavy Chains