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 inhibitors 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 different 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 prevented 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 calcineurin inhibitors for 2 weeks following TAC.