Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.
BACKGROUND
Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.


RESULTS
Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment.


CONCLUSIONS
The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.
Shimoyama
M
M
Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, and the Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Hayashi
D
D
Takimoto
E
E
Zou
Y
Y
Oka
T
T
Uozumi
H
H
Kudoh
S
S
Shibasaki
F
F
Yazaki
Y
Y
Nagai
R
R
Komuro
I
I
D000818:Animals; D001012:Aorta, Abdominal / Q000503:physiopathology / Q000601:surgery; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001810:Blood Volume; D001835:Body Weight; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000517:prevention & control*; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D016559:Tacrolimus