PTEN inhibitor improves vascular remodeling and cardiac function after myocardial infarction through PI3k/Akt/VEGF signaling pathway

Feng, Qiuting; Li, Xing; Qin, Xian; Yu, Changhong; Jin, Yan; Qian, Xiaojun

doi:10.1186/s10020-020-00241-8

Cited by 31 publications

(20 citation statements)

References 45 publications

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“… Liang et al (2020) have reported that cardiac-specific PTEN knockout can reduce the inflammatory response and fibrotic remodeling to protect the heart after MI injury. Several researches reported the increased expression of PTEN in MI ( Parajuli et al, 2012 ; Feng et al, 2020 ), which were consistent with our results. As PTEN was reported to play roles in cell apoptosis and survival through PI3K/AKT pathway ( Wu et al, 2006 ; Mocanu and Yellon, 2007 ), PTEN reducing became a potential therapeutic target for increasing myocardial survival ( Oudit et al, 2004 ; Liang et al, 2021b ).…”

Section: Discussionsupporting

confidence: 93%

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Zhou

Wang

et al. 2022

Front. Genet.

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Background: Acute myocardial infarction (AMI) is one of the main fatal diseases of cardiovascular diseases. Circular RNA (circRNA) is a non-coding RNA (ncRNA), which plays a role in cardiovascular disease as a competitive endogenous RNA (ceRNA). However, their role in AMI has not been fully clarified. This study aims to explore the mechanism of circRNA-related ceRNA network in AMI, and to identify the corresponding immune infiltration characteristics.Materials and Methods: The circRNA (GSE160717), miRNA (GSE24548), and mRNA (GSE60993) microarray datasets of AMI were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) were identified by the “limma” package. After integrating the circRNA, miRNA and mRNA interaction, we constructed a circRNA-miRNA-mRNA network. The “clusterProfiler” package and String database were used for functional enrichment analysis and protein-protein interaction (PPI) analysis, respectively. After that, we constructed a circRNA-miRNA-hub gene network and validated the circRNAs and mRNAs using an independent dataset (GSE61144) as well as qRT-PCR. Finally, we used CIBERSORTx database to analyze the immune infiltration characteristics of AMI and the correlation between hub genes and immune cells.Results: Using the “limma” package of the R, 83 DEcircRNAs, 54 DEmiRNAs, and 754 DEmRNAs were identified in the microarray datasets of AMI. Among 83 DEcircRNAs, there are 55 exonic DEcircRNAs. Then, a circRNA-miRNA-mRNA network consists of 21 DEcircRNAs, 11 DEmiRNAs, and 106 DEmRNAs were predicted by the database. After that, 10 hub genes from the PPI network were identified. Then, a new circRNA-miRNA-hub gene network consists of 14 DEcircRNAs, 7 DEmiRNAs, and 9 DEmRNAs was constructed. After that, three key circRNAs (hsa_circ_0009018, hsa_circ_0030569 and hsa_circ_0031017) and three hub genes (BCL6, PTGS2 and PTEN) were identified from the network by qRT-PCR. Finally, immune infiltration analysis showed that hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI.Conclusion: Our study constructed a circRNA-related ceRNA networks in AMI, consists of hsa_circ_0031017/hsa-miR-142-5p/PTEN axis, hsa_circ_0030569/hsa-miR-545/PTGS2 axis and hsa_circ_0009018/hsa-miR-139-3p/BCL6 axis. These three hub genes were significantly positively correlated with up-regulated immune cells (neutrophils, macrophages and plasma cells) in AMI. It helps improve understanding of AMI mechanism and provides future potential therapeutic targets.

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Section: Discussionsupporting

confidence: 93%

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Zhou

Wang

et al. 2022

Front. Genet.

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“…In contrast, stimulating angiogenesis ameliorates cardiac remodeling after myocardial infarction (Laan et al 2009 ). CD31 plays an important role in endothelial cell intercellular junctions and is widely used as a marker for angiogenesis quantification (Feng et al 2020 ; Ho et al 2012 ). We, therefore, assessed the de novo formation of microvessel in peri-infarct myocardium at 14 days post-MI through CD31 staining and expression.…”

Section: Resultsmentioning

confidence: 99%

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Tang

Zhang

et al. 2021

Mol Med

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Background It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. Methods Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 μg/Kg body weight/day, 100 μL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. Results We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. Conclusion Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

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“…PTEN has been extensively studied in tumor development and angiogenesis, but increasing evidence demonstrated that PTEN was also closely related to cardiovascular disease ( Parajuli et al, 2012 ). It was reported that the inhibition of PTEN cannot only reduce cardiomyocyte apoptosis, oxidative stress, and DNA damage in ischemic injury ( Gong et al, 2021 ) but also shrink infarction areas and improve cardiac function in MI mice ( Feng et al, 2020 ). We observed that the expression of PTEN in both protein and mRNA in H9c2 cells have risen sharply after H/R injury, but was restrained by SW-exo and miR-140-3p.…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Cardiac Shock Wave-Induced Exosome Derived From Endothelial Colony-Forming Cells Carrying miR-140-3p Alleviate Cardiomyocyte Hypoxia/Reoxygenation Injury via the PTEN/PI3K/AKT Pathway

Yang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Background: Stem cell-derived exosomes have great potential in the treatment of myocardial ischemia–reperfusion injury (IRI). Extracorporeal cardiac shock waves (ECSW) as effective therapy, in part, could activate the function of exosomes. In this study, we explored the effect of ECSW-induced exosome derived from endothelial colony-forming cells on cardiomyocyte hypoxia/reoxygenation (H/R) injury and its underlying mechanisms.Methods: The exosomes were extracted and purified from the supernatant of endothelial colony-forming cells (ECFCs-exo). ECFCs-exo treated with shock wave (SW-exo) or without shock wave (CON-exo) were performed with high-throughput sequencing of the miRNA. H9c2 cells were incubated with SW-exo or CON-exo after H/R injury. The cell viability, cell apoptosis, oxidative stress level, and inflammatory factor were assessed. qRT-PCR was used to detect the expression levels of miRNA and mRNA in cells and exosomes. The PTEN/PI3K/AKT pathway-related proteins were detected by Western blotting, respectively.Results: Exosomes secreted by ECFCs could be taken up by H9c2 cells. Administration of SW-exo to H9c2 cells after H/R injury could significantly improve cell viability, inhibit cell apoptosis, and downregulate oxidative stress level (p < 0.01), with an increase in Bcl-2 protein and a decrease in Bax, cleaved caspase-3, and NF-κB protein (p < 0.05). Notably, miR-140-3p was found to be highly enriched both in ECFCs and ECFCs-exo treated with ECSW (p < 0.05) and served as a critical mediator. SW-exo increased miR-140-3p expression but decreased PTEN expression in H9c2 cells with enhanced phosphorylation of the PI3K/AKT signaling pathway. These cardioprotective effects of SW-exo on H/R injury were blunted by the miR-140-3p inhibitor. Dual-luciferase assay verified that miR-140-3p could directly target the 3′UTR of PTEN mRNA and exert a negative regulatory effect.Conclusion: This study has shown the potential of ECSW as an effective stimulation for the exosomes derived from ECFCs in vitro. SW-exo exerted a stronger therapeutic effect on H/R injury in H9c2 cells possibly via delivering exosomal miR-140-3p, which might be a novel promising strategy for the myocardial IRI.

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PTEN inhibitor improves vascular remodeling and cardiac function after myocardial infarction through PI3k/Akt/VEGF signaling pathway

Cited by 31 publications

References 45 publications

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Construction and Bioinformatics Analysis of circRNA-miRNA-mRNA Network in Acute Myocardial Infarction

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Extracorporeal Cardiac Shock Wave-Induced Exosome Derived From Endothelial Colony-Forming Cells Carrying miR-140-3p Alleviate Cardiomyocyte Hypoxia/Reoxygenation Injury via the PTEN/PI3K/AKT Pathway

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