Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications.
Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer, but novel biomarkers for early diagnosis are lacking. Extensive effort has been exerted to identify miRNA biomarkers in LUAD. Unfortunately, high inter-lab variability and small sample sizes have produced inconsistent conclusions in this field. To resolve the above-mentioned limitations, we performed a comprehensive analysis based on LUAD miRNome profiling studies using the robust rank aggregation (RRA) method. Moreover, miRNA-gene interaction network, pathway enrichment analysis and Kaplan-Meier survival curves were used to investigate the clinical values and biological functions of the identified miRNAs. A total of six common differentially expressed miRNAs (DEMs) were identified in LUAD. An independent cohort further confirmed that four miRNAs (miR-21-5p, miR-210-3p, miR-182-5p and miR-183-5p) were up-regulated and two miRNAs (miR-126-3p and miR-218-5p) were down-regulated in LUAD tissues. Pathway enrichment analysis also suggested that the above-listed six DEMs may affect LUAD progression via the estrogen signaling pathway. Survival analysis based on the TCGA dataset revealed the potential prognostic values of six DEMs in patients with LUAD (P-value<0.01). In conclusion, we identified a panel of six miRNAs from LUAD using miRNome profiling studies. Our results provide evidence for the use of these six DEMs as novel diagnostic and prognostic biomarkers for LUAD patients.
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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.
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