Document Detail

Calcineurin in human heart hypertrophy.
MedLine Citation:
PMID:  12010908     Owner:  NLM     Status:  MEDLINE    
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. METHODS AND 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.
Oliver Ritter; Susanne Hack; Kai Schuh; Nicola Röthlein; Andreas Perrot; Karl J Osterziel; Hagen D Schulte; Ludwig Neyses
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Circulation     Volume:  105     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-05-15     Completed Date:  2002-05-24     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2265-9     Citation Subset:  AIM; IM    
Department of Medicine, University of Wuerzburg, Germany.
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MeSH Terms
Aortic Valve Stenosis / metabolism
Blotting, Western
Calcineurin / genetics,  metabolism*
Cardiomegaly / metabolism*
Cardiomyopathy, Hypertrophic / metabolism
DNA-Binding Proteins / metabolism
Enzyme Activation
Myocardium / metabolism
NFATC Transcription Factors
Nuclear Proteins*
Protein Structure, Tertiary
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transcription Factors / metabolism
Reg. No./Substance:
0/DNA-Binding Proteins; 0/NFATC Transcription Factors; 0/Nuclear Proteins; 0/RNA, Messenger; 0/Transcription Factors; EC
Comment In:
Circulation. 2002 May 14;105(19):2242-3   [PMID:  12010903 ]

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