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Abstract
While neurohumoral antagonists improve outcomes in heart failure (HF), cardiac remodeling and dysfunction progress and outcomes remain poor. Therapies superior or additive to standard HF therapy are needed. Pharmacologic mTOR inhibition by rapamycin attenuated adverse cardiac remodeling and dysfunction in experimental heart failure (HF). However, these studies used rapamycin doses that produced blood drug levels targeted for primary immunosuppression in human transplantation and therefore the immunosuppressive effects may limit clinical translation. Further, the relative or incremental effect of rapamycin combined with standard HF therapies targeting upstream regulators of cardiac remodeling (neurohumoral antagonists) has not been defined. Our objectives were to determine if anti-remodeling effects of rapamycin were preserved at lower doses and whether rapamycin effects were similar or additive to a standard HF therapy (angiotensin receptor blocker (losartan)). Experimental murine HF was produced by transverse aortic constriction (TAC). At three weeks post-TAC, male mice with established HF were treated with placebo, rapamycin at a dose producing immunosuppressive drug levels (target dose), low dose (50% target dose) rapamycin, losartan or rapamycin + losartan for six weeks. Cardiac structure and function (echocardiography, catheterization, pathology, hypertrophic and fibrotic gene expression profiles) were assessed. Downstream mTOR signaling pathways regulating protein synthesis (S6K1 and S6) and autophagy (LC3B-II) were characterized. TAC-HF mice displayed eccentric hypertrophy, systolic dysfunction and pulmonary congestion. These perturbations were attenuated to a similar degree by oral rapamycin doses achieving target (13.3±2.1 ng/dL) or low (6.7±2.5 ng/dL) blood levels. Rapamycin treatment decreased mTOR mediated regulators of protein synthesis and increased mTOR mediated regulators of autophagy. Losartan monotherapy did not attenuate remodeling, whereas Losartan added to rapamycin provided no incremental benefit over rapamycin alone. These data lend support to investigation of low dose rapamycin as a novel therapy in human HF.
Highlights
Over six million Americans have heart failure (HF) and while treatment with renin-angiotensin-aldosterone system (RAAS) antagonists and b-adrenergic antagonists improve outcomes in HF, progressive cardiac remodeling and dysfunction occur on standard therapy and outcomes are poor [1,2,3]
In concert with its role in protein synthesis, mTORC1 localization and signaling is involved in the regulation of autophagy [9]. mTORC1 signaling is sensitive to pharmacological inhibition by rapamycin, a macrolide that binds FK-binding protein 12 (FKBP12) to form a drug-protein complex that can bind to and inhibit Mechanistic target of rapamycin (mTOR) present within mTORC1
This dose achieved trough serum rapamycin levels (13.860.8 ng/mL) similar to those targeted when rapamycin is used for primary immunosuppression in human transplant recipients (7–15 ng/ml; [11])
Summary
Over six million Americans have heart failure (HF) and while treatment with renin-angiotensin-aldosterone system (RAAS) antagonists and b-adrenergic antagonists improve outcomes in HF, progressive cardiac remodeling and dysfunction occur on standard therapy and outcomes are poor [1,2,3]. Mechanistic target of rapamycin (mTOR) is a kinase that plays a significant role in broad signaling networks related to protein synthesis, cell cycle progression, autophagy and actin organization (reviewed in [6]). While FKBP12rapamycin does not bind mTOR present within an mTORC2 complex, there is evidence that prolonged rapamycin therapy may inhibit mTORC2 by limiting integration of de novo synthesized mTOR into mTORC2. This occurs in a cell specific manner in vitro and in normal heart tissue after rapamycin administration in vivo [10], the dose used for in vivo studies (10 mg/kg intraperitoneally, IP) was quite high relative to other in vivo studies (2 mg/kg IP, below)
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