MiR-223-3p as a Novel MicroRNA Regulator of Expression of Voltage-Gated K+ Channel Kv4.2 in Acute Myocardial Infarction

Xue, Lingui; Zhang, Ying; Du, Weijie; Liang, Haihai; He, Hua; Zhang, Lu; Pan, Zhenwei; Li, Xuelian; Xu, Chaoqian; Zhou, Yuhong; Wang, Leimin; Qian, Ming; Liu, Tianyi; Yin, Hongli; Lu, Yanjie; Yang, Baofeng; Shan, Hongli

doi:10.1159/000445609

Cited by 60 publications

(53 citation statements)

References 51 publications

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“…Both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts subjected to I/R, in which they cooperatively suppressed necroptosis [35]. Liu et al reported that miR-223 was upregulated in a rat model of AMI and that its overexpression can promote arrhythmias; thus, miR-223 may be a new target in the treatment of ischemic arrhythmias [36]. The abovementioned studies elucidated the roles of miR-223 in various cardiac diseases, focusing specifically on the roles of miR-223 in various metabolic, hypertrophic and necrotic processes; however, they did not investigate whether or not miR-223 impacts cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

Liu¹,

Xu²,

Deng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Percutaneous coronary intervention reduces acute myocardial infarction (MI)-induced mortality to a great extent, but effective treatments for MI-induced cardiac fibrosis and heart failure are still lacking. MicroRNAs (miRNAs) play a variety of roles in cells and have thus been investigated extensively. MicroRNA-223 (miR-223) expression has been reported to be altered in post-MI heart failure in humans; however, the roles of miR-223 in MI remain unknown. Our study aimed to elucidate the roles of miR-223 in cardiac fibrosis. Methods: Cultured cardiac fibroblasts (CFs) were activated by TGF-β1 stimulation. Gain and loss of miR-223 and RAS p21 protein activator 1 (RASA1) knockdown in CFs were achieved by transfecting the cells with miR-223 mimics and inhibitors, as well as small interfering RNA-RASA1 (siRASA1), respectively. Quantitative real-time reverse transcriptase-polymerase chain reactions (qRT-PCR) was used to determine miR-223-3p and RASA1 expression levels, and Cell Counting Kit-8 (CCK-8), transwell migration and scratch assays were performed to assess CFs viability and migration, respectively. Western blotting was used to detect collagen I, collagen III, alpha-smooth muscle actin (a-SMA), RASA1, p-Akt/t-Akt, p-MEK1/2/t-MEK1/2, and p-ERK1/2/t-ERK1/2 protein expressions, and immunofluorescence assays were used to detect the expression of α-actin, vimentin and α-SMA. Luciferase assays were carried out to determine whether miR-223 binds to RASA1. Rat models of MI were established by the ligation of the left anterior descending (LAD) coronary artery. MiR-223 inhibition in vivo was achieved via intramyocardial injections of the miR-223 sponge carried by adeno-associated virus 9 (AAV9). The cardiac function was detected by echocardiography, and cardiac fibrosis was shown by Masson’s trichrome staining. Results: miR-223 was increased in CFs compared to cardiomypcytes, and TGF-β1 treatment increased miR-223 expression in CFs. The miR-223 mimics enhanced cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression in CFs, while the miR-223 inhibitors had contrasting effects and partially prevented the promoting effects of TGF-β1. qRT-PCR and western blotting revealed that miR-223 negatively regulated RASA1 expression, and the luciferase assays showed that miR-223 suppressed the luciferase activity of the RASA1 3’ untranslated region (3'UTR), indicating that miR-223 binds directly to RASA1. Similar to transfection with the miR-223 mimics, RASA1 knockdown enhanced cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression in CFs. Moreover, RASA1 knockdown partially reversed the inhibitory effects of the miR-223 inhibitor on cell proliferation and migration and collagen I, collagen III, and α-SMA protein expression, indicating that the effects of miR-223 in CFs are partially mediated by the regulation of RASA1 expression. Further exploration showed that miR-223 mimics and siRASA1 promoted MEK1/2, ERK1/2 and AKT phosphorylation, while the mi...

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Section: Discussionmentioning

confidence: 99%

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

Liu¹,

Xu²,

Deng³

et al. 2018

Cell Physiol Biochem

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“…4A-C ). Two other microRNAs, miR-223-3p and miR-301a-3p, were shown to regulate Kv4.2 in the heart (Panguluri et al, 2013, Liu et al, 2016), but their function in neurons and during seizures is unknown.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

et al. 2016

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Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure-suppressive. MiR-324-5p inhibition also blocks kainic acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic acid-induced seizure onset in wild type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.

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“…Zhi et al showed that miR-223 was shown to inhibit bladder cancer cell migration and invasion by downregulating its target ZEB1 [25]. In addition, miR-223 was shown to be a potential target for the treatment of ischemic arrhythmias, as miR-223 repressed the expression of the voltage-gated K+ channel Kv4.2 [26]. miR-223 suppresses cardiomyocyte hypertrophy by modulating the expression of its target TNNI3K, a troponin interacting kinase [27].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-873 is a Potential Serum Biomarker for the Detection of Ectopic Pregnancy

Yan²,

Xu³

et al. 2017

Cell Physiol Biochem

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Background: Ectopic pregnancy (EP) refers to the implantation of the zygote outside the uterine cavity. In clinical practice, the diagnosis of EP relies on a combination of ultrasound findings and serum human chorionic gonadotrophin (hCG) measurements. However, the need for serial hCG measurements increases the risk of tubal rupture and death, underscoring the need to identify biomarkers for the early detection of EP. Methods: The serum concentrations of 21 microRNAs (miRNAs) associated with pregnancy or with known placental expression, as well as serum hCG and progesterone levels were analyzed 36 patients with viable intrauterine pregnancy (VIP), 30 patients with spontaneous abortion (SA), and 34 patients with EP using specific assay kits and reverse transcription PCR. The diagnostic performance of the different serum markers for detecting EP was analyzed by ROC curve analysis. Results: Five miRNAs were differentially expressed between the three groups, of which miR-873 and miR-223 were significantly lower in EP than in VIP and SA patients and did not change significantly according to gestational age, and miR-323 was significantly higher in EP than in VIP and SA. As a single marker, miR-873 had the highest sensitivity for detecting EP at 61.76% (at a fixed specificity of 90%). In comparison, the combination of hCG, progesterone and miR-873 had the highest sensitivity for detecting EP at 79.41% (at a fixed specificity of 90%). Conclusion: Although further validation in large-scale prospective studies is necessary, our results suggest that miR-873 could be a valuable noninvasive and stable biomarker for the early detection of EP.

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MiR-223-3p as a Novel MicroRNA Regulator of Expression of Voltage-Gated K+ Channel Kv4.2 in Acute Myocardial Infarction

Cited by 60 publications

References 51 publications

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

MicroRNA-223 Regulates Cardiac Fibrosis After Myocardial Infarction by Targeting RASA1

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

MicroRNA-873 is a Potential Serum Biomarker for the Detection of Ectopic Pregnancy

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