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SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodeling; however, the pathogenesis of the disease is not completely understood. Sirtuin 1 (SIRT1) is a histone deacetylase involved in cell survival and metabolism. The present study explored the potential role of SIRT1 in human pulmonary arterial endothelial cells (HPAECs) under hypoxic conditions. In vitro HPAECs were cultured and exposed to hypoxic conditions. Subsequently, SIRT1 expression levels were measured via western blotting, the generation of reactive oxygen species (ROS) was evaluated, and the interaction between SIRT1 and Akt was assessed via reverse transcription-quantitative PCR and western blotting. In addition, the effects of SIRT1 on cell proliferation and apoptosis were also investigated. The results indicated that hypoxia induced SIRT1 expression in pulmonary arterial endothelial cells, which may be associated with ROS generation. SIRT1 expression activated the Akt signaling pathway, which increased the expression levels of Bcl-2 and hypoxia-inducible factor-1 in HPAECs. Moreover, SIRT1 promoted HPAEC proliferation and inhibited HPAEC apoptosis. ROS generation enhanced the SIRT1/Akt axis, which was essential for epithelial cell injury under hypoxic conditions. Therefore, blocking SIRT1 may reduce hypoxia-induced pathological damage in HPAECs.

SUBMITTER: Xi L

PROVIDER: S-EPMC7579766 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway.

Xi Liandong L Ruan Lin L Yao Xiaoguang X Zhang Dong D Yuan Hongwei H Li Qiang Q Yan Cuihuan C

Experimental and therapeutic medicine 20201012 6

Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodeling; however, the pathogenesis of the disease is not completely understood. Sirtuin 1 (SIRT1) is a histone deacetylase involved in cell survival and metabolism. The present study explored the potential role of SIRT1 in human pulmonary arterial endothelial cells (HPAECs) under hypoxic conditions. <i>In vitro</i> HPAECs were cultured ...[more]

PMID: 33101469

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Project description:Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target.

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SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway.

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SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway.

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