McNair Benjamin D, Schlatter Jacob A, Cook Ross F, Yusifova Musharraf, Bruns Danielle R
Division of Kinesiology & Health, University of Wyoming, Laramie, WY, United States of America.
Division of Kinesiology & Health, University of Wyoming, Laramie, WY, United States of America.
Exp Gerontol. 2021 Aug;151:111395. doi: 10.1016/j.exger.2021.111395. Epub 2021 May 7.
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.
雷帕霉素对哺乳动物雷帕霉素靶蛋白（mTOR）的抑制作用可减轻心力衰竭（HF）以及左心室（LV）功能的年龄相关变化。基于在年轻的肺动脉高压（PH）模型中mTOR信号升高的报道，雷帕霉素也被提议作为治疗肺动脉高压（PH）及伴发的右心衰竭（PH-RHF）的药物。然而，尽管右心室（RV）功能可预测与年龄相关的心力衰竭以及包括PH在内的几种肺部疾病状态下的生存率，但雷帕霉素尚未在衰老、PH和右心疾病的背景下进行测试。因此，我们使用低压缺氧（HH）诱导的PH和右心室（RV）重塑的小鼠模型，测试了雷帕霉素治疗可减轻老年小鼠缺氧性PH-RHF的假说。暴露于HH导致体重显著下降，雷帕霉素会加剧这种情况。HH增加了肺和RV重量、RV壁厚度以及RV收缩功能障碍，这可通过RV每搏输出量和心输出量得到证明。虽然雷帕霉素挽救了雄性小鼠的肺动脉加速时间，但它通常并未改善其他心肺重塑或功能指标。正如预期的那样，HH诱导了RV和肺中缺氧调节基因的表达；然而，这种转录激活被雷帕霉素减弱，这代表了在慢性缺氧情况下雷帕霉素对老年RV有害的一种潜在机制。总之，我们证明雷帕霉素不是老年小鼠缺氧性PH的可行治疗方法，可能是由于在这种情况下体重下降加剧。我们建议未来的研究应考虑RV和LV之间的差异以及在与年龄相关疾病背景下mTOR与缺氧之间的相互作用。
