Abstract 13698: Effect of Dose and Standard Therapy on the Anti-Remodeling Effects of Rapamycin in Experimental Heart Failure
Effect of Dose and Standard Therapy on the Anti-remodeling Effects of Rapamycin in Experimental Heart Failure
Introduction: MTOR inhibition with rapamycin attenuates adverse cardiac remodeling in experimental heart failure (HF). We sought to determine if rapamycin’s anti-remodeling effect is seen at blood levels targeted for immunosuppression in transplantation subjects and if angiotensin II receptor type-1 or beta-adrenergic receptor blockade has incremental benefit when added to rapamycin.
Methods: Male C57BL/6 mice underwent transverse aortic constriction (TAC) and 3 weeks later, echocardiography. TAC mice with HF (EF<65% by echo which correlates with adverse remodeling and increased lung weight at subsequent autopsy) at the 3 week echo were randomized to oral therapy with: rapamycin (4 mg/kg/day or 8 mg/kg/day), rapamycin (8 mg/kg/day) plus losartan or plus propranolol for 6 wks. Trough serum rapamycin levels, S6 Kinase 1 (S6k1) phosphorylation at Thr 389, an index of mTOR activity and cAMP dependent protein kinase regulatory I (PKA reg I) and PKA Catalytic-α expression, to assess beta-adrenergic signaling were measured.
Results: Table. Rapamycin treated HF mice had amelioration of adverse remodeling and HF severity (lung weights) associated with inhibition of downstream mTOR signaling (decreased S6k1 phosphorylation) and down-regulated PKA signaling (decreased PKA Reg I and PKA Catalytic-α expression). The addition of losartan or propranolol to rapamycin had no incremental effect.
Conclusion: mTOR inhibition with rapamycin, at serum levels at the lower and upper range of transplant targeted immunosuppression, reversed LV remodeling in severe established HF. Angiotensin II receptor type-1 or beta-adrenergic receptor blockade have no additional benefit suggesting mTOR signaling is a central regulator of remodeling in HF downstream of adrenergic and angiotensin signaling input.
- © 2012 by American Heart Association, Inc.