title: Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice.
abstract: Cardiomyocyte hypertrophy occurs in response to a variety of physiological and pathological stimuli. While pathological hypertrophy in heart failure is usually coupled with depressed contractile function, physiological hypertrophy associates with increased contractility. In the present study, we explored whether 8 weeks of moderate intensity exercise training would lead to a cardiac anti-remodelling effect in an experimental model of heart failure associated with a deactivation of a pathological (calcineurin/NFAT, CaMKII/HDAC) or activation of a physiological (Akt-mTOR) hypertrophy signalling pathway. The cardiac dysfunction, exercise intolerance, left ventricle dilatation, increased heart weight and cardiomyocyte hypertrophy from mice lacking alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO mice) were associated with sympathetic hyperactivity induced heart failure. The relative contribution of Ca(2+)-calmodulin high-affinity (calcineurin/NFAT) and low-affinity (CaMKII/HDAC) targets to pathological hypertrophy of alpha(2A)/alpha(2C)ARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in alpha(2A)/alpha(2C)ARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in alpha(2A)/alpha(2C)ARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in alpha(2A)/alpha(2C)ARKO mice. Exercise training improved cardiac function and exercise capacity in alpha(2A)/alpha(2C)ARKO mice and decreased heart weight and cardiomyocyte width paralleled by diminished nuclear NFATc3 and GATA-4 translocation as well as GATA-4 expression levels. When combined, these findings support the notion that deactivation of calcineurin/NFAT pathway-induced pathological hypertrophy is a preferential mechanism by which exercise training leads to the cardiac anti-remodelling effect in heart failure.
authors.affiliation: School of Physical Education and Sport, University of Sao Paulo, SP, Brazil.
authors.forename: R S F
authors.initials: RS
authors.lastname: Oliveira
authors.forename: J C B
authors.initials: JC
authors.lastname: Ferreira
authors.forename: E R M
authors.initials: ER
authors.lastname: Gomes
authors.forename: N A
authors.initials: NA
authors.lastname: Paixão
authors.forename: N P L
authors.initials: NP
authors.lastname: Rolim
authors.forename: A
authors.initials: A
authors.lastname: Medeiros
authors.forename: S
authors.initials: S
authors.lastname: Guatimosim
authors.forename: P C
authors.initials: PC
authors.lastname: Brum
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017079:Exercise Tolerance / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C547769:Adra2a protein, mouse; C547775:Adra2c protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; D018341:Receptors, Adrenergic, alpha-2; D016572:Cyclosporine; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D019703:Calcineurin