Abstract 11460: MicroRNA-1 and MicroRNA-133a Elevations in Serum of Patients with Cardiovascular Disease Indicate the Existence of Myocardial Damage
Background: Recently, it has been reported that microRNAs (miRNAs or miRs) stably exist in exosomes of blood, and muscle-specific miRNA levels increase in the serum of patients with acute myocardial infarction (MI). However, it is still unclear whether miRNAs are released from cardiomyocytes into blood. The purpose of this study was to identify the significance, source, and function of elevated circulating miRNAs.
Methods and Results: We first measured the serum levels of muscle-specific miR-1 and miR-133a in patients with cardiovascular diseases (n=71). These miRNAs increased significantly in patients with acute coronary syndrome (ACS) (n=29) compared with non-ACS (n=42) (miR-1: 0.1×10-11 ± 0.0 vs. 4.8×10-11 ± 2.3×10-11, p<0.0005; miR-133a: 0.6×10-11 ± 0.2×10-11 vs. 39.3×10-11 ± 18.4×10-10, p<0.0001). Classifying the patients according to their disease, miR-133a levels were elevated in patients not only with acute MI but also with unstable angina pectoris (n=8, p<0.05) and Takotsubo cardiomyopathy (n=6, p<0.005). Furthermore, miR-1 and miR-133a levels were correlated with the cTnT levels in serum (miR-1: p<0.005, R=0.327; miR-133a: p<0.0001, R=0.624). In ROC analysis, areas under the curve of miR-1 and miR-133a were 0.777 and 0.932, respectively. To evaluate the expression changes of miRNAs in the infarcted heart, we investigated the levels of miR-1 and miR-133a in a mouse MI model. Both miRNAs significantly decreased in border and infarcted regions (n=6, p<0.01). Next, to examine if miR-133a can be released from cardiomyocytes, we stimulated H9c2 cardiomyoblast cells with calcium-ionophore, and confirmed that miR-133a was elevated in exosomes of the medium dose-dependently. However, the elevation of miR-133a in exosomes was not observed at the low concentrations when there was no induction of cell death. Finally, we also found that miR-133a-containing exosomes significantly reduced the luciferase activity of 293T cells transfected with a miR-133a-sensor vector (n=3, p<0.05).
Conclusions: Circulating miR-1 and miR-133a can be used as biomarkers of myocardial damage. In addition, our results suggest that elevated levels of circulating miR-133a originate mainly from the injured myocardium, and it may have functions in other cells or organs.
- © 2011 by American Heart Association, Inc.