MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

Kang, Gyeoung Jin; Xie, An; Liu, Hong; Dudley, Samuel C.

doi:10.1172/jci.insight.140759

Cited by 14 publications

(6 citation statements)

References 42 publications

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“…Suffer from arrhythmias and HCM in the future 52 . SCN5A plays a vitally important role in the cardiac electrical conduction and arrhythmic risk, a study provided a new effective therapy to reduce arrhythmia through downregulating the expression of SCN5A 53 . Coincidentally, there is a study reported that a combination of quinidine/mexiletine reduces arrhythmia in patients with SCN5A gene mutation 54 .…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Liang

Rui

et al. 2020

Preprint

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Background: Dingji Fumai decoction (DFD), a traditional herbal mixture, has been widely used to ventricular arrhythmia (VA) in clinical practice in China. However, research on the bioactive components and underlying mechanisms of DFD in VA is still scarce. Methods: Components of DFD were collected from TCMSP, ETCM, and literature. Then, the chemical structures of each component were obtained from PubChem. Next, SwissADME and SwissTargetPrediction were applied for compounds screening and targets prediction of DFD, meanwhile, targets of VA were collected from DrugBank and OMIM. Then, the H-C-T-D network as well as the PPI network were constructed based on the data obtained above. CytoNCA was utilized to filter hub genes and VarElect was used to analyze the relationship between genes and diseases. At last, Metascape was employed for systematic analysis on the potential targets of herbals against VA, and AutoDock was applied for molecular docking to verify the results.Results: A total of 434 components were collected, 168 of which were qualified, and there were 28 shared targets between DFD and VA. Three function modules of DFD were found from the PPI network. Further systematic analysis of shared genes and function modules explained the potential mechanism of DFD in the treatment of VA, molecular docking has verified the interactions. Conclusions: DFD could be employed for VA through mechanisms, including complex interactions between related components and targets, as predicted by network pharmacology and molecular docking. This work confirmed DFD could apply for the treatment of VA and promoted the explaining of DFD for VA in the molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Liang

Rui

et al. 2020

Preprint

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“…Raffaele Coppini conducted a cohort study of patients with hypertrophic cardiomyopathy (HCM), the outcome indicated that, among patients with HCM, most patients have a mutation in TNNT2, and these patients are more likely to suffer from arrhythmias and HCM in the future [ 51 ]. SCN5A is pivotal to cardiac electrical conduction and arrhythmic risk; a study provided a new effective therapy to reduce arrhythmia through downregulating the expression of SCN5A [ 52 ]. Similarly, there is a study that reported that a combination of quinidine/mexiletine reduces arrhythmia in patients with SCN5A gene mutation [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Liang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Dingji Fumai Decoction (DFD), a traditional herbal mixture, has been widely used to ventricular arrhythmia (VA) in clinical practice in China. However, research on the bioactive components and underlying mechanisms of DFD in VA is still scarce. Methods. Components of DFD were collected from TCMSP, ETCM, and literature. The chemical structures of each component were obtained from PubChem. Next, SwissADME and SwissTargetPrediction were applied for compounds screening and targets prediction of DFD; meanwhile, targets of VA were collected from DrugBank and Online Mendelian Inheritance in Man (OMIM). Then, the H-C-T-D network and the protein-protein interaction (PPI) network were constructed based on the data obtained above. CytoNCA was utilized to filter hub genes and VarElect was used to analyze the relationship between genes and diseases. At last, Metascape was employed for systematic analysis on the potential targets of herbals against VA, and AutoDock was applied for molecular docking to verify the results. Results. A total of 434 components were collected, 168 of which were qualified, and there were 28 shared targets between DFD and VA. Three function modules of DFD were found from the PPI network. Further systematic analysis of shared genes and function modules explained the potential mechanism of DFD in the treatment of VA; molecular docking has verified the interactions. Conclusions. DFD could be employed for VA through mechanisms, including complex interactions between related components and targets, as predicted by network pharmacology and molecular docking. This work confirmed that DFD could apply to the treatment of VA and promoted the explanation of DFD for VA in the molecular mechanisms.

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“…For miR-448, no alteration in the brain following stroke was reported, nor a connection to ischemic stroke and blood levels. A study utilizing a spinal cord ischemia/reperfusion injury model reported increased levels of miR-448 measured by qRT-PCR [ 44 ] and in cell hypoxic culture models of myocardial infarction [ 31 , 45 ]. The studies, as mentioned above, on miRNA alteration in ischemic stroke have either been performed in the cerebral cortex, the blood serum, or the researchers did not indicate the exact location.…”

Section: Discussionmentioning

confidence: 99%

Transient Focal Cerebral Ischemia Leads to miRNA Alterations in Different Brain Regions, Blood Serum, Liver, and Spleen

Voelz

Ebrahimy

Zhao

et al. 2021

IJMS

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Ischemic stroke is characterized by an occlusion of a cerebral blood vessel resulting in neuronal cell death due to nutritional and oxygen deficiency. Additionally, post-ischemic cell death is augmented after reperfusion. These events are paralleled by dysregulated miRNA expression profiles in the peri-infarct area. Understanding the underlying molecular mechanism in the peri-infarct region is crucial for developing promising therapeutics. Utilizing a tMCAo (transient Middle Cerebral Artery occlusion) model in rats, we studied the expression levels of the miRNAs (miR) 223-3p, 155-5p, 3473, and 448-5p in the cortex, amygdala, thalamus, and hippocampus of both the ipsi- and contralateral hemispheres. Additionally, the levels in the blood serum, spleen, and liver and the expression of their target genes, namely, Nlrp3, Socs1, Socs3, and Vegfa, were assessed. We observed an increase in all miRNAs on the ipsilateral side of the cerebral cortex in a time-dependent manner and increased miRNAs levels (miR-223-3p, miR-3473, and miR-448-5p) in the contralateral hemisphere after 72 h. Besides the cerebral cortex, the amygdala presented increased expression levels, whereas the thalamus and hippocampus showed no alterations. Different levels of the investigated miRNAs were detected in blood serum, liver, and spleen. The gene targets were altered not only in the peri-infarct area of the cortex but selectively increased in the investigated non-affected brain regions along with the spleen and liver during the reperfusion time up to 72 h. Our results suggest a supra-regional influence of miRNAs following ischemic stroke, which should be studied to further identify whether miRNAs are transported or locally upregulated.

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MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

Abstract: GJK and SCD have submitted a provisional patent (patent application no. 63/012,351) entitled, "Compositions and methods for increasing sodium current in cardiac cells," which has been filed for the use of an antagomir to MIR448 as an antiarrhythmic therapy.

Cited by 14 publications

References 42 publications

Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Network Pharmacology-Based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

Transient Focal Cerebral Ischemia Leads to miRNA Alterations in Different Brain Regions, Blood Serum, Liver, and Spleen

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