Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation.
Atrial tachyarrhythmia (AF) alters intracellular calcium homeostasis and induces cellular hypertrophy of atrial myocytes. The impact of the calcium-dependent calcineurin pathway on the development of AF-induced atrial hypertrophy has not yet been analyzed. In this study, atrial tissue samples from patients with sinus rhythm and chronic persistent atrial fibrillation (CAF) were used to determine changes in expression and activity of calcineurin A (CnA), and its relation to CnA-regulated transcription factors NFATc1-4, and hypertrophic markers ANP, troponin I, and beta-MHC. CnA phosphatase activity and CnAbeta protein contents were significantly upregulated in patients with CAF. Calcineurin activation led to dephosphorylation, redistribution, and subsequent accumulation of NFATc3 in nuclei during CAF, and expression of hypertrophic genes was increased. CAF-dependent changes were reproduced by ex vivo pacing (2-4 Hz) of human atrial tissue slices. FK506 abolished the hypertrophic response induced by electrical-field stimulation. Atrial tachyarrhythmia causes atrial hypertrophy by activation of the CnA signal pathway, which thereby contributes to structural remodeling of human atria.
Bukowska
A
A
Institute of Experimental Internal Medicine, University Hospital Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Lendeckel
U
U
Hirte
D
D
Wolke
C
C
Striggow
F
F
Röhnert
P
P
Huth
C
C
Klein
H U
HU
Goette
A
A
D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism; D001281:Atrial Fibrillation / Q000378:metabolism*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013610:Tachycardia / Q000378:metabolism
D012333:RNA, Messenger; D019703:Calcineurin