miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart

Li, Na; Hwangbo, Cheol; Jaba, Irina M.; Zhang, Jiasheng; Papangeli, Irinna; Han, Joungho; Mikush, Nicole; Larrivée, Bruno; Eichmann, Anne; Chun, Hyung J.; Young, Lawrence H.; Tı̂rziu, Daniela

doi:10.1038/srep21228

Cited by 37 publications

(30 citation statements)

References 43 publications

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“…Furthermore, a 3′ UTR-containing fragment of mouse BCAT2 was amplified and cloned into the luciferase reporter plasmid to detect the luciferase activity. The luciferase activity was significantly downregulated by miR-182 ( Figure 6C ), consistent with the results of a previous report (Li et al, 2016). Meanwhile, protein levels of BCAT2 were significantly decreased in cortical neurons overexpressing miR-182 ( Figure 6D ), but the expression of BCAT2 increased when blocking the endogenous miR-182 by the inhibitor ( Figure 6E ).…”

Section: Resultssupporting

confidence: 92%

“…We found that BCAT2 expression was significantly downregulated by miR-182 ( Figure 6B ). BCAT2 is known to be a target of miR-182 in PIGF mice and mouse embryonic fibroblasts (Li et al, 2016). Furthermore, a 3′ UTR-containing fragment of mouse BCAT2 was amplified and cloned into the luciferase reporter plasmid to detect the luciferase activity.…”

Section: Resultsmentioning

confidence: 99%

“…BCAT2 is a kind of BCATm, which are ubiquitously presented in all tissues in the mitochondria of cells (Hull et al, 2012). It is a newly identified target of miR-182 that negatively regulates AKT activity, and BCAT2 depletion results in a significant increase in cardiomyocyte size and phosphorylation of AKT (S473) (Li et al, 2016). In our study, we investigated the functions of miR-182 in axon outgrowth and dendrite branching out of cortical neurons, and demonstrated that BCAT2/PTEN/AKT pathway might participate in the regulation of neuron maturation.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

Wang

Lü

et al. 2017

Front. Cell. Neurosci.

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MicroRNAs are implicated in neuronal development and maturation. Neuronal maturation, including axon outgrowth and dendrite tree formation, is regulated by complex mechanisms and related to several neurodevelopmental disorders. We demonstrated that one neuron-enriched microRNA, microRNA-182 (miR-182), played a significant role in regulating neuronal axon outgrowth and dendrite tree formation. Overexpression of miR-182 promoted axon outgrowth and complexity of the dendrite tree while also increasing the expression of neurofilament-M and neurofilament-L, which provide structural support for neurite outgrowth. However, a reduction of miR-182 inhibited neurite outgrowth. Furthermore, we showed that miR-182 activated the AKT pathway by increasing AKT phosphorylation on S473 and T308 and inhibiting PTEN activity by increasing phosphorylation on S380. Inhibition of AKT activity with the PI3-K inhibitor LY294002 could downregulate AKT and PTEN phosphorylation and suppress axon outgrowth. In addition, we showed that BCAT2 might be the target of miR-182 that takes part in the regulation of neuronal maturation; blockage of endogenous BCAT2 promotes axon outgrowth and AKT activity. These observations indicate that miR-182 regulates axon outgrowth and dendrite maturation involving activation of the PTEN/AKT pathway.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

Wang

Lü

et al. 2017

Front. Cell. Neurosci.

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“…can act as an oncogene in several types of cancers [32,33]. Only a few previous studies investigated the functions of miR-182 in the heart, which indicated that miR-182 was related to cardiac hypertrophy [34,35]. In addition, a previous study showed that miR-182-5p could protected H9c2 cells from hypoxia-induced apoptosis [24].…”

Section: Discussionmentioning

confidence: 99%

Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p

Zhang¹,

Chu²,

Liu³

2018

Cell Physiol Biochem

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Background/Aims: Ganoderic acid A (GAA) isolated from Ganoderma lucidum, shows various benefit activities, such as anti-tumor activity, anti-HIV activity and hepatoprotective activity. However, the potential effects of GAA on hypoxia-induced injury of cardiomyocytes are still unclear. In this study, we aimed to reveal the effects of GAA on hypoxic-induced H9c2 cell injury, as well as potential underlying molecular mechanisms. Methods: Rat H9c2 cardiomyocytes were cultured in hypoxia condition with different doses of GAA. Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. qRT-PCR was performed to assess the expression levels of microRNA-182-5p (miR-182-5p) and phosphatase and tensin homologue (PTEN). Cell transfection was conducted to change the expression levels of miR-182-5p and PTEN in H9c2 cells. Finally, protein levels of key factors involved in cell proliferation, cell apoptosis and PTEN/PI3K/AKT pathway were evaluated using western blotting. Results: Hypoxia treatment significantly induced H9c2 cell viability loss and apoptosis. GAA incubation remarkably protected H9c2 cells from hypoxia-induced viability loss, proliferation inhibition and apoptosis. In addition, GAA obviously enhanced the expression level of miR-182-5p in H9c2 cells. Suppression of miR-182-5p notably alleviated the protective effects of GAA on hypoxia-treated H9c2 cells. Furthermore, miR-182-5p negatively regulated the mRNA and protein levels of PTEN in H9c2 cells. GAA attenuated hypoxia-induced inactivation of PI3K/AKT pathway in H9c2 cells by up-regulating miR-182-5p and then down-regulating PTEN. Conclusion: GAA protected rat H9c2 cardiomyocytes from hypoxia-induced injury might via up-regulating miR-182-5p, down-regulating PTEN and then activating PI3K/AKT signaling pathway.

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“…PLSR analysis gave quantitative outputs to how likely each microRNA was involved in our response. Certain microRNA’s identified by our anaylsis have been shown to regulate important function like fibrosis (miR-27a and miR-29c 26, 27 ), cardiac hypertrophy (miR-29c 28 , miR-96 29, 30 , miR-182 31, 32 and miR-185 33 ), angiogenesis (miR-27a 34 ), and apoptotsis (miR-138 35, 36 , miR-25 37 ). Although, our model is predictive of microRNA-based mechanism, these targets still need to be validated in the future studies.…”

Section: Discussionmentioning

confidence: 93%

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

145

153

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Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. Objective We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Methods and Results Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.

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miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart

Cited by 37 publications

References 43 publications

MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

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