RUNX1: an emerging therapeutic target for cardiovascular disease

Riddell, Alexandra; McBride, Martin W.; Braun, Thomas; Nicklin, Stuart A.; Cameron, Ewan R.; Loughrey, Christopher M.; Martin, Tamara P.

doi:10.1093/cvr/cvaa034

Cited by 60 publications

(58 citation statements)

References 186 publications

(242 reference statements)

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“…14j). The role of RUNX1 has been primarily studied in cardiomyocytes 41 where deficiency protects against ischemic injury 42 . In the heart, the role of RUNX1 in non-myocytes is not defined in detail yet one recent study has reported the RUNX1 binding motif as a main motif in cardiac fibroblast-specific active enhancers 43 .…”

Section: The Direction Of the Trajectory Was Further Confirmed By An mentioning

confidence: 99%

Spatial multi-omic map of human myocardial infarction

Kuppe

Flores

et al. 2020

Preprint

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Myocardial infarction is a leading cause of mortality. While advances in the acute treatment have been made, the late-stage mortality is still high, driven by an incomplete understanding of cardiac remodeling processes1,2. Here we used single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of different physiological zones and timepoints of human myocardial infarction and human control myocardium to generate an integrative high-resolution map of cardiac remodeling. This approach allowed us to increase spatial resolution of cell-type composition and provide spatially resolved insights into the cardiac transcriptome and epigenome with identification of distinct cellular zones of injury, repair and remodeling. We here identified and validated mechanisms of fibroblast to myofibroblast differentiation that drive cardiac fibrosis. Our study provides an integrative molecular map of human myocardial infarction and represents a reference to advance mechanistic and therapeutic studies of cardiac disease.

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Section: The Direction Of the Trajectory Was Further Confirmed By An mentioning

confidence: 99%

Spatial multi-omic map of human myocardial infarction

Kuppe

Flores

et al. 2020

Preprint

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“…Runx1 also regulates the development and transcription during hematopoiesis [ 19 – 21 ]. Recently, Runx1 was demonstrated to be involved in the processes underlying adverse cardiac remodeling [ 22 ], and Runx1 activation in cardiomyocytes after MI is harmful to ventricular function [ 23 ]. However, to date, the protective role of Runx1 against adverse cardiac remodeling after MI in response to dihydrolycorine treatment remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction

Huang

Pan

et al. 2021

Oxidative Medicine and Cellular Longevity

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In spite of early interventions to treat acute myocardial infarction (MI), the occurrence of adverse cardiac remodeling following heart failure due to acute MI remains a clinical challenge. Thus, there is an increasing demand for the development of novel therapeutic agents capable of inhibiting the development of pathological ventricular remodeling. RNA-seq data analysis of acute MI rat models from GEO revealed that Runx1 was the most differentially expressed MI-related gene. In this study, we demonstrated that increased Runx1 expression under pathological conditions results in decreased cardiac contractile function. We identified dihydrolycorine, an alkaloid lycorine, as a promising inhibitor of Runx1. Our results showed that treatment with this drug could prevent adverse cardiac remodeling, as indicated by the downregulation of fibrotic genes using western blotting (collagen I, TGFβ, and p-smad3), downregulation of the apoptosis gene Bax, upregulation of the apoptosis gene Bcl-2, and improved cardiac functions, such as LVEF, LVSF, LVESD, and LVEDD. Additionally, dihydrolycorine treatment could rescue cardiomyocyte hypertrophy as demonstrated by wheat germ agglutinin staining, increased expression levels of the punctuate gap junction protein connexin 43, and decreased α-SMA expression, resulting in cardiomyocyte fibrosis in immunofluorescence staining. Molecular docking, binding modeling, and pull-down assays were used to identify potential dihydrolycorine-binding sites in Runx1. When Ad-sh-Runx1 was transfected into hypoxia-cardiomyocytes or injected into the hearts of MI rats, the cardioprotective effects of dihydrolycorine were abolished, and the normal electrophysiological activity of cardiomyocytes was disrupted. Taken together, the results of the present study indicate that dihydrolycorine may inhibit adverse cardiac remodeling after MI through the reduction of Runx1, suggesting that dihydrolycorine-mediated-Runx1 regulation might represent a novel therapeutic approach for adverse cardiac remodeling after MI.

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“…RUNX1 upregulation is related to impaired cardiac contractile function and cardiac remodeling ( McCarroll et al, 2018 ). Runx1 knock-out can protect against adverse cardiac remodeling after AMI in mice ( Riddell et al, 2020 ). Moreover, Runx1 mRNA expression increases in the blood of AMI patients ( Mao et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Regulatory circRNAs Involved in the Pathogenesis of Acute Myocardial Infarction

et al. 2021

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BackgroundAcute myocardial infarction (AMI) has high morbidity and mortality worldwide. However, the pathogenesis of AMI is still unclear, and the impact of circular RNAs (circRNAs) on AMI has rarely been recognized and needs to be explored.Materials and MethodsThe circRNA array was applied to investigate the expression level of circRNAs in the blood samples of coronary arteries of three AMI patients and three normal persons. Principal component analysis (PCA) and unsupervised clustering analysis were performed to reveal the distinguished expression patterns of circRNAs. The miRNA expression profiles of AMI patients were identified from a public dataset from the Gene Expression Omnibus (GEO) database (GSE31568). The miRNA binding sites on the circRNAs were predicted by miRanda. The miRNA enrichment analysis and annotation tool were used to explore the pathways that the dysregulated circRNAs may participate in.ResultsIn total, 142 differentially expressed circRNAs, including 89 upregulated and 53 downregulated in AMI samples, were identified by the differential expression analysis. AMI patients had quite different circRNA expression profiles to those of normal controls. Functional characterization revealed that circRNAs that had the potential to regulate miRNAs were mainly involved in seven pathways, such as the Runt-related transcription factor-1 (RUNX1) expression and activity-related pathway. Specifically, hsa_circRNA_001654, hsa_circRNA_091761, hsa_circRNA_405624, and hsa_circRNA_406698 were predicted to sponge four miRNAs including hsa-miR-491-3p, hsa-miR-646, hsa-miR-603, and hsa-miR-922, thereby regulating RUNX1 expression or activity.ConclusionWe identified dysregulated blood circRNAs in the coronary arteries of AMI patients and predicted that four upregulated circRNAs were involved in the regulation of RUNX1 expression or activity through sponging four miRNAs.

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RUNX1: an emerging therapeutic target for cardiovascular disease

Cited by 60 publications

References 186 publications

Spatial multi-omic map of human myocardial infarction

Spatial multi-omic map of human myocardial infarction

Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction

Identification of Regulatory circRNAs Involved in the Pathogenesis of Acute Myocardial Infarction

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