Inhibition of mTOR by rapamycin does not improve hypoxic pulmonary hypertension-induced right heart failure in old mice.
Exp Gerontol
; 151: 111395, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-33971279
ABSTRACT
Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin attenuates heart failure (HF) and age-associated changes in left ventricular (LV) function. Rapamycin has also been suggested as a therapy for pulmonary hypertension (PH) and concomitant right heart failure (PH-RHF) based on reports of elevated mTOR signaling in young models with PH. However, rapamycin has yet to be tested in the setting of aging, PH, and right heart disease despite the fact that RV function predicts survival in both age-related HF as well as several pulmonary disease states including PH. Thus we tested the hypothesis that rapamycin treatment would attenuate hypoxic PH-RHF in old mice using a mouse model of hypobaric hypoxia (HH)-induced PH and right ventricular (RV) remodeling. Exposure to HH resulted in significant loss of body weight which was exacerbated by rapamycin. HH elevated lung and RV weight, RV wall thickness as well as RV systolic dysfunction as evidenced by RV stroke volume and cardiac output. While rapamycin rescued pulmonary artery acceleration time in males, it generally did not improve other indexes cardiopulmonary remodeling or function. As expected, HH induced expression of hypoxia-regulated genes in the RV and the lungs; however, this transcriptional activation was attenuated by rapamycin, representing a potential mechanism by which rapamycin is detrimental in the aged RV in the setting of chronic hypoxia. Together, we demonstrate that rapamycin is not a viable therapeutic in hypoxic PH in old mice, likely due to exacerbated loss of body weight in this setting. We suggest that future efforts should take into consideration the differences between the RV and LV and the interaction between mTOR and hypoxia in the setting of age-related disease.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Disfunção Ventricular Direita
/
Insuficiência Cardíaca
/
Hipertensão Pulmonar
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Exp Gerontol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos