Small molecule-mediated up-regulation of microRNA targeting a key cell death modulator BNIP3 improves cardiac function following ischemic injury

Lee, Seyeon; Lee, Seahyoung; Choi, Eun Kyoung; Ham, Ok Kyung; Lee, Chang Youn; Lee, Jiyun; Seo, Ho Seong; Cha, Min‐Ji; Mun, Bohyun; Lee, Yun-Mi; Yoon, Cheesoon; Hwang, Ki‐Chul

doi:10.1038/srep23472

Cited by 19 publications

(18 citation statements)

References 44 publications

(46 reference statements)

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“…35) MiR-182 prevents ischemiainduced cardiac cell death by suppressing BNIP3 expression. 36) The above mentioned findings suggest that downregulating the expression of pro-apoptotic BNIP3 is beneficial for cell survival.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3

Diao

Liu

Shi

et al. 2017

Bioscience, Biotechnology, and Biochemistry

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Oxidative stress-induced myocardial apoptosis and necrosis are involved in ischemia/reperfusion (I/R) injury. This study was performed to investigate microRNA (miR)-210's role in oxidative stress-related myocardial damage. The expression of miR-210 was upregulated in myocardial tissues of I/R rats, while that of Bcl-2 adenovirus E1B 19kDa-interacting protein 3 (BNIP3) was downregulated. To simulate in vivo oxidative stress, H9c2 cells were treated with HO for 48 h. MiR-210 level was increased upon HO stimulation, peaked at 8 h, and then decreased. An opposite expression pattern of BNIP3 was observed. BNIP3 was demonstrated as a direct target of miR-210 via luciferase reporter assay. HO-induced cell apoptosis was attenuated by miR-210 mimics, whereas aggravated by miR-210 inhibitor. MiR-210 knockdown-induced cell apoptosis in presence of HO was attenuated by BNIP3 siRNA. Our work demonstrates that miR-210 plays a protective role in HO-induced cardiomyocyte apoptosis at least by regulating the pro-apoptotic BNIP3.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3

Diao

Liu

Shi

et al. 2017

Bioscience, Biotechnology, and Biochemistry

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“…The Bcl-2 interacting protein 3 (BNIP3) 3′-untranslated region (UTR) containing complementary sequences or the mutated sequence for the seed sequence of miR-182 was amplified by PCR as described previously (25), and cloned into the firefly luciferase expressing vector, pGL3 (Promega Corporation); the vectors were denoted as wild-type (wt) pGL3-BNIP3-3′-UTR and mutant (mut) BNIP3-3′-UTR, respectively. For the luciferase reporter assay, 293T cells (American Type Culture Collection) were seeded into a 24-well plate (5.0×10 5 /well) and transfected with the wt or mut reporter vector, together with miR-182 mimics or miR-182 inhibitor using Lipofectamine 2000.…”

Section: Methodsmentioning

confidence: 99%

Tetramethylpyrazine protects retinal ganglion cells against H2O2‑induced damage via the�microRNA‑182/mitochondrial pathway

Wang

Ren

et al. 2019

Int J Mol Med

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Glaucoma is the leading cause of irreversible blindness worldwide; the apoptosis of the retinal ganglion cells (RGCs) is a hallmark of glaucoma. Tetramethylpyrazine (TMP) is the main active component of Ligusticum wallichii Franchat , and has been demonstrated to improve a variety of injuries through its antioxidative and antiapoptotic properties. However, these effects of TMP on glaucoma have not been studied. The present study aimed to investigate the potential role of TMP in glaucoma and to elucidate its possible mechanisms responsible for these effects. An in vitro model was generated, in which primary RGCs (PRGCs) were treated with H 2 O 2 . Our study revealed that TMP protected against H 2 O 2- induced injury to PRGCs, as evidenced by enhanced cell viability, reduced caspase 3 activity and decreased cell apoptosis. We also reported that TMP treatment inhibited reactive oxygen species (ROS) production and malondialdehyde levels, but upregulated the antioxidative enzyme superoxide dismutase. In particular, TMP significantly increased the expression of microRNA-182-5p (miR-182) in H 2 O 2 -treated PRGCs, which was selected as the target miRNA for further research. In addition, our findings suggested that the protective effects of TMP on H 2 O 2 -induced injury were attenuated by knockdown of miR-182. The results of a luciferase reporter assay demonstrated that Bcl-2 interacting protein 3 (BNIP3), an effector of mitochondria-mediated apoptosis, was a direct target of miR-182. In addition, TMP treatment significantly decreased the expression of BNIP3, Bax, cleaved-caspase-3 and cleaved-poly(ADP-ribose)polymerase, but increased that of Bcl-2. Also, TMP treatment decreased the release of cytochrome c from mitochondria and improved mitochondrial membrane potential in H 2 O 2 -treated RGCs. Of note, the inhibitory effects of TMP on the mitochondrial apoptotic pathway were suggested to be reversed by knockdown of miR-182. Collectively, our findings provide novel evidence that TMP protects PRGCs against H 2 O 2 -induced damage through suppressing apoptosis and oxidative stress via the miR-182/mitochondrial apoptotic pathway.

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“…16 The disruption of BNIP3 inhibits apoptosis, is crucial for ischemic cardiomyocytes, and is important for cardiac cell survival 16, 17, 18, 19, 20. We also reported that downregulating BNIP3 is an effective means to prevent cardiac cell death 21 . Nevertheless, inhibition of necroptosis or apoptosis remains limited as a therapeutic treatment in heart disease.…”

Section: Introductionmentioning

confidence: 98%

Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury

Shin¹,

Choi

Moon

et al. 2019

Molecular Therapy - Nucleic Acids

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Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease.

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Small molecule-mediated up-regulation of microRNA targeting a key cell death modulator BNIP3 improves cardiac function following ischemic injury

Cited by 19 publications

References 44 publications

MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3

MicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3

Tetramethylpyrazine protects retinal ganglion cells against H2O2‑induced damage via the�microRNA‑182/mitochondrial pathway

Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury

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