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. METHODS AND 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.
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. METHODS AND 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.
Authors: B A Rothermel; T A McKinsey; R B Vega; R L Nicol; P Mammen; J Yang; C L Antos; J M Shelton; R Bassel-Duby; E N Olson; R S Williams Journal: Proc Natl Acad Sci U S A Date: 2001-03-13 Impact factor: 11.205
Authors: L J De Windt; H W Lim; O F Bueno; Q Liang; U Delling; J C Braz; B J Glascock; T F Kimball; F del Monte; R J Hajjar; J D Molkentin Journal: Proc Natl Acad Sci U S A Date: 2001-03-13 Impact factor: 11.205
Authors: Pasi Tavi; Sampsa Pikkarainen; Jarkko Ronkainen; Perttu Niemelä; Mika Ilves; Matti Weckström; Olli Vuolteenaho; Joseph Bruton; Håkan Westerblad; Heikki Ruskoaho Journal: J Physiol Date: 2003-10-17 Impact factor: 5.182