Prediction of Coronary Artery Disease by Measurement of Circulating MicroRNA-423-3p Levels

In this issue of the Journal, Wang et al demonstrate that circulating microRNA (miRNA; miR)-423-3p can improve the prediction of primary coronary artery disease (CAD) outcomes on the basis of a traditional risk factor model in the general population.¹ First, they screened miRNA candidates to distinguish CAD from healthy controls using serum from patients with CAD and from control subjects. They utilized peripheral blood mononuclear cells (PBMCs) from control participants and vascular endothelial cells (ECs) treated with or without hypoxia to improve the specificity for screening. Next, the qualifying candidate miRNAs were measured in different samples collected from other hospitals, and the most reproducible – miR-10a-5p and miR-423-3p – were then measured in a large-scale general population. Thus, circulating miR-423-3p was found to improve the prediction of primary CAD outcomes on the basis of a traditional risk factor model.

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The miRNAs constitute a class of small non-coding RNAs that inhibit protein expression by base pairing with complementary sequences located within the 3′ untranslated region of target mRNAs.^2–4 miRNAs circulate in the blood stream enclosed in small vesicles called exosomes.^5,6 Thus, these circulating miRNAs are stable in the blood, and there are several established methods for their extraction and measurement. There are already many reports, including ours, that show circulating miRNAs are good biomarkers for cardiovascular diseases.^7–10

Because there are many circulating miRNAs, it is relatively difficult to select an important and useful miRNA for the prediction of cardiovascular diseases. One of the reasons for the success of this study is through its application of 2 different in vitro assays for the selection of candidate miRNAs, which enabled the authors to improve the specificity of their candidates (Figure). It is of note that utilization of these assays led to the findings on the source and mechanism of release of miR-423-3p. They showed that reduced miR-423-3p expression in ECs and in exosomes in EC culture medium after stimulation with tumor necrosis factor-α compared with control ECs and EC medium. They proposed that low production of miR-423-3p after inflammatory stimuli is the mechanism for serum changes in the levels of miR-423-3p in patients with CAD. However, miR-423-3p was also enriched in PBMCs, as shown in their data from the candidate screening. Therefore, further precise investigations are required to elucidate the source of miR-423-3p and the mechanisms for its production and release. It is already reported that circulating miR-423-5p can be used for circulating biomarker for heart failure.¹¹ Because miR-423-5p is expressed with miR-423-3p and is expected to be more stable (http://www.mirbase.org/cgi-bin/mirna_entry.pl?acc=hsa-mir-423), it is interesting to investigate the levels of miR-423-5p in the same samples.

Figure.

Flow chart of the experimental strategy of this study. CAD, coronary artery disease; ECs, endothelial cells; PBMCs, peripheral blood mononuclear cells.

The other key success factor is that they confirmed their results in different groups of patients. They validated the results of their candidate miRNAs in 2 populations and finally evaluated the predictive ability of CAD in a large cohort. Because miR-423-3p is expressed in PBMCs and ECs, it is possible that miR-423-3p may be utilized for the prediction of other atherosclerotic diseases. It will also be interesting to determine whether there are similar results in other ethnic groups. As the authors indicate, it was reported that a combination of several miRNAs increased the predictive power for acute myocardial infarction.^12,13 Moreover, plasma miR-423-3p is reported to be upregulated in patients with prostate cancer.¹⁴ Thus, the addition of other biomarkers into the assessment might be beneficial for the prediction of cardiovascular diseases.

This study contains new information about potential serum biomarker for patients with CAD. However, the function of miR-423-3p is still not completely understood, especially in the development of atherosclerosis. It will be interesting to elucidate the roles of miR-423-3p in ECs and PBMCs by the generation of tissue-specific miR-423-deficient mice.

Financial Disclosures

None.

Disclosure

K.O. is a member of Circulation Journal ’ Editorial Team.

References

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