BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

Yang, Wenbo; Wu, Zhijun; Yang, Ke; Yang, Han; Chen, Yanjia; Zhao, Weilin; Huang, Fanyi; Yao, Jin; Jin, Wei

doi:10.1152/ajpheart.00487.2018

Cited by 64 publications

(61 citation statements)

References 31 publications

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“…They regulate not only metabolic processes such as protein synthesis and glycolysis/gluconeogenesis [32,33] but also cell growth, cycle progression and cell division, proliferation, and apoptosis [34][35][36][37]. Currently, the PI3K pathway is receiving increasing attention, and far more significant functions are being revealed [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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Background: PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods: The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results: By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions: The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

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Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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“…These are the essential cellular pathways of mitochondrial protein synthesis, significantly relevant to the cardiac remodeling and heart failure [53,54]. Furthermore, pathways of programmed cell death (e.g, Apoptotic Execution Phase) and PTEN regulation (e.g., Regulation of PTEN Stability and Activity), which were previously reported as important factors of cardiac remodeling and homeostasis [53,55–58], were detected solely by DCEC in two-directional and one-directional change clusters, respectively. Supplemental Tables S6–S8 list the unique pathways enriched by K-means, HC, PAM, LSTM-VAE, and DCEC in one-directional change, two-directional change and late change clusters, respectively.…”

Section: Resultsmentioning

confidence: 99%

Unsupervised classification of multi-omics data during cardiac remodeling using deep learning

Chung

Mirza

Choi

et al. 2019

Methods

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Integration of multi-omics in cardiovascular diseases (CVDs) presents high potentials for translational discoveries. By analyzing abundance levels of heterogeneous molecules over time, we may uncover biological interactions and networks that were previously unidentifiable. However, to effectively perform integrative analysis of temporal multi-omics, computational methods must account for the heterogeneity and complexity in the data. To this end, we performed unsupervised classification of proteins and metabolites in mice during cardiac remodeling using two innovative deep learning (DL) approaches. First, long short-term memory (LSTM)-based variational autoencoder (LSTM-VAE) was trained on time-series numeric data. The low-dimensional embeddings extracted from LSTM-VAE were then used for clustering. Second, deep convolutional embedded clustering (DCEC) was applied on images of temporal trends. Instead of a two-step procedure, DCEC performes a joint optimization for image reconstruction and cluster assignment. Additionally, we performed K-means clustering, partitioning around medoids (PAM), and hierarchical clustering. Pathway enrichment analysis using the Reactome knowledgebase demonstrated that DL methods yielded higher numbers of significant biological pathways than conventional clustering algorithms. In particular, DCEC resulted in the highest number of enriched pathways, suggesting the strength of its unified framework based on visual similarities. Overall, unsupervised DL is shown to be a promising analytical approach for integrative analysis of temporal multi-omics.

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“…Our present study found that miR-132 targeted PTEN in CFs, which is supported by previous study [ 22 ]. The signal pathway of PI3K/Akt was involved in the fibrosis of the heart [ 37 , 38 ]. The expression of p-Akt was increased in the CFs treated by Ang II [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-132 attenuated cardiac fibrosis in myocardial infarction-induced heart failure rats

Wang

Ruan

et al. 2020

Bioscience Reports

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The aim of the present study was to determine the effect of microRNA (miR)-132 on cardiac fibrosis in myocardial infarction (MI)-induced heart failure and angiotensin (Ang) II-treated cardiac fibroblasts (CFs). Experiments were carried out in Sprague-Dawley rat treatment with ligation of left coronary artery to induce heart failure, and in CFs administration of Ang II to induce fibrosis. The level of miR-132 was increased in the heart of rats with MI-induced heart failure and the Ang II-treated CFs. In MI rats, left ventricle (LV) ejection fraction, fractional shortening, the maximum of the first differentiation of LV pressure (LV +dp/dtmax) and decline (LV -dp/dtmax) and LV systolic pressure (LVSP) were reduced, and LV end-systolic diameter (LVESD), LV end-diastolic diameter (LVEDD), LV volumes in systole (LVVS) and LV volumes in diastole (LVVD) were increased, which were reversed by miR-132 agomiR but deteriorated by miR-132 antagomiR. The expression levels of collagen I, collagen III, transforming growth factor-β (TGF-β), and α-smooth muscle actin (α-SMA) were increased in the heart of rat with MI-induced heart failure and CFs administration of Ang II. These increases were inhibited by miR-132 agomiR but enhanced by miR-132 antagomiR treatment. MiR-132 inhibited PTEN expression, and attenuated PI3K/Akt signal pathway in CFs. These results indicated that the upregulation of miR-132 improved the cardiac dysfunction, attenuated cardiac fibrosis in heart failure via inhibiting PTEN expression, and attenuating PI3K/Akt signal pathway. Upregulation of miR-132 may be a strategy for the treatment of heart failure and cardiac fibrosis.

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BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

Cited by 64 publications

References 31 publications

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Unsupervised classification of multi-omics data during cardiac remodeling using deep learning

MicroRNA-132 attenuated cardiac fibrosis in myocardial infarction-induced heart failure rats

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