Mammalian target of rapamycin overexpression antagonizes chronic hypoxia-triggered pulmonary arterial hypertension via the autophagic pathway

Abstract

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disorder with high morbidity and mortality, and is characterized by excessive growth of endothelial cells. Recently, the mammalian target of rapamycin (mTOR) has attracted increasing attention due to its potential as a therapeutic target against certain diseases associated with proliferative and metabolic abnormalities. However, the effect on mTOR on PAH has not yet been elucidated. In the present study, a marked downregulation of mTOR was observed in PAH patients. Following construction of a mouse model of PAH by chronic exposure to hypoxia, adenovirus-mediated upregulation of mTOR significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy and wall thickness of pulmonary arterioles, indicating a protective effect of mTOR on PAH. Further analysis confirmed that mTOR overexpression inhibited autophagy triggered by hypoxia through blocking light chain 3 II expression and increasing p62 levels. In vitro, hypoxia enhanced the proliferation of human pulmonary artery endothelial cells (PAECs), which was markedly abrogated by mTOR overexpression. Of note, upregulation of mTOR inhibited the hypoxia-induced autophagy pathway, which contributed to cell proliferation, while silencing of autophagy by RNA interference with ATG5 significantly inhibited cell proliferation. In conclusion, the results of the present study suggested a potential protective effect of mTOR on the progression of PAH by suppressing PAEC proliferation through blocking the autophagic pathway. Therefore, the present study suggested that mTOR is a promising therapeutic agent against PAH.

Up‐regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension

“…Raptor or mTOR as a potential treatment target in PAH has been tested previously in various experimental models of PAH (44) and, recently, in a small clinical study (45). However, the therapeutic efficacy of these interventions in PAH varies across reports, and off-target drug effects have emerged as an important consideration due to the functionality of mTOR in numerous tissue types, in particular in systemic blood vessels (45).…”

β-Arrestins1 inhibit autophagy induced by hypoxic injury in human pulmonary artery endothelial cells via Akt/mTOR signaling pathway

“…(28) Previous study showed that mTOR repressed the autophagy in PAH (29) . Li et al (12) also indicated that mTOR ameliorated hypoxia-triggered PAH by autophagypathway. Our results further showed that hypoxia reduced the expressions level of p-Akt and p-mTOR in hPAECs.…”

“…Hypoxia-induced activation of autophagy gained more insight on PAH. Li et al (12) observed that pulmonary vascular remodeling was followed by autophagy activation via downregulation of mTOR in PAH patients and hypoxia-induced PAH mice. Paradoxically, study demonstrated that light chain-3B(LC3B) partially inhibited the proliferation of PAECs (13) , suggesting autophagy might suppress vascular remodeling.…”

Autophagy in pulmonary hypertension: Emerging roles and therapeutic implications

“…Many environmental factors can increase or decrease the levels of autophagy in PAECs (Goncharov et al, 2014;Li et al, 2015). mTOR, which has a potential protection on the progression of PH, suppresses PAECs proliferation by blocking the autophagic pathway (Kato et al, 2017;Li et al, 2015).…”

“…Many environmental factors can increase or decrease the levels of autophagy in PAECs (Goncharov et al, 2014;Li et al, 2015). mTOR, which has a potential protection on the progression of PH, suppresses PAECs proliferation by blocking the autophagic pathway (Kato et al, 2017;Li et al, 2015). Moreover, the number of autophagosomes or autolysosomes increased in human PAECs upon combined treatment with morphine and the HIV protein Tat, and promoting these cells triggered apoptosis, which resulted in the development of a proliferative phenotype (Dalvi et al, 2016).…”