title: Calcineurin in human heart hypertrophy.
abstract: BACKGROUND
  In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure.
  
  
  RESULTS
  We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue.
  
  
  CONCLUSIONS
  Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.
authors: Department of Medicine, University of Wuerzburg, Germany.
authors: Oliver
authors: O
authors: Ritter
authors: Susanne
authors: S
authors: Hack
authors: Kai
authors: K
authors: Schuh
authors: Nicola
authors: N
authors: Röthlein
authors: Andreas
authors: A
authors: Perrot
authors: Karl J
authors: KJ
authors: Osterziel
authors: Hagen D
authors: HD
authors: Schulte
authors: Ludwig
authors: L
authors: Neyses
mesh_terms: D001024:Aortic Valve Stenosis / Q000378:metabolism; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D019703:Calcineurin