Role of Calcineurin-Dependent Signaling Pathway on the Left Ventricular Hypertrophy Induced by Pressure Overload

Abstract

Background and Objectives:Calcineurin-dependent transcriptional pathway has recently been implicated in cardiac hypertrophy. Whether calcineurin inhibition can prevent the development of pressure-overload left ventricular hypertrophy (LVH is still controversial. To elucidate this issue, the effects of calcineurin inhi- bitors on the prevention of pressure-overload LVH were examined in mice. Materials and Methods:Pressure overload was induced by transverse aortic contriction (TAC in 57 ICR mice. Three different doses of CsA (TAC/CsA group, n=21 and FK506 (TAC/FK group, n=20 were administered subcutaneously from -2 to 14 days after surgery and 16 mice were treated with vehicle (TAC group. Another 60 mice were sham-operated and treated with CsA (CsA group, n=19, FK506 (FK group, n=18 or vehicle (Control group, n=23. Results:Two weeks after TAC, the LV weight-to-body weight (LVW/BW ratio was not significantly diff- erent among the Control, CsA and FK groups although it was greater in the TAC group (4.55±0.69 mg/g than in the Control (2.78±0.70 mg/g and other sham-operated groups (p<0.00005. Low-dose CsA (5 mg/ kg/day or FK506 (0.6 mg/kg/day injection following TAC did not decrease the LVW/BW ratio. However, intermediate-dose and high-dose CsA (25 and 50 mg/kg/day or FK506 (2 and 6 mg/kg/day treatment preve- nted pressure-overload induced LVH and the degree of LVH inhibition was dose-dependent. Interstitial and/or perivascular fibrosis was remarkably decreased by the administration of intermediate and high doses of cal- cineurin inhibitors for 2 weeks following TAC. Conclusion:Taken together, calcineurin inhibitors, CsA and FK506, attenuated pressure-overload LVH response in a dose-dependent fashion. This data indicates that a