Target of Rapamycin (TOR)-Based Therapy for Cardiomyopathy: Evidence from Zebrafish and Human Studies
- Authors
- Kushwaha, S., and Xu, X.
- ID
- ZDB-PUB-120807-1
- Date
- 2012
- Source
- Trends in cardiovascular medicine 22(2): 39-43 (Review)
- Registered Authors
- Xu, Xiaolei
- Keywords
- none
- MeSH Terms
-
- Animals
- Cardiomyopathies/drug therapy*
- Cardiomyopathies/genetics
- Cardiomyopathies/pathology
- Humans
- Immunosuppressive Agents/therapeutic use*
- Rodentia
- Signal Transduction
- Sirolimus/therapeutic use*
- TOR Serine-Threonine Kinases*
- Zebrafish
- PubMed
- 22841839 Full text @ Trends Cardiovasc. Med.
Rapamycin is a U.S. Food and Drug Administration–approved drug for the prevention of immunorejection following organ transplantation. Pharmacological studies suggest a potential new application of rapamycin in attenuating cardiomyopathy, but the potential for this application is not yet supported by genetic studies of genes in target of rapamycin (TOR) signaling in rodents. Recently, supporting genetic evidence was presented in zebrafish using two adult cardiomyopathy models. By characterizing a heterozygous zebrafish target of rapamycin (ztor) mutant, the therapeutic effect of long-term TOR signaling inhibition was demonstrated. Dose- and stage-dependent functions of TOR signaling provide an explanation for the seemingly contradictory results obtained in genetic studies of TOR components in rodents. The results from the zebrafish studies, together with the supporting preliminary clinical studies, suggested that TOR signaling inhibition should be further pursued as a novel therapeutic strategy for cardiomyopathy. Future directions for developing TOR-based therapy include assessing the long-term benefits of rapamycin as a candidate drug for heart failure patients, defining the dynamic activity of TOR, exploring the impacts of TOR signaling manipulation in different models of cardiomyopathies, and elucidating the downstream signaling branches that confer the therapeutic effects of TOR signaling inhibition.