Down-regulation of miR-133a/b in patients with myocardial infarction correlates with the presence of ventricular fibrillation
Introduction
MicroRNAs (miRNA) are important regulators of physiologic and pathologic conditions of the heart. However, certain miRNAs may be expressed in a tissue-specific pattern, e.g., miR-1 and miR-133a/b being expressed in a muscle-specific and miR-208 in a cardiac-specific pattern (myo-miRs). Although encoded as a bicistronic cluster, there is increasing evidence that expression of miR-1 and miR-133 in the heart can differ depending on the stage and etiology of the heart disease. The two miRNAs can demonstrate opposite direction of changes in their expression, between hypertrophic hearts and ischemic myocardium [1,2].
In myocardial infarction (MI), deregulation of muscle- and cardiac-specific miRNAs contributes to the myocardial contractile function [3], as well as to arrhythmias [4]. Life-threatening cardiac arrhythmias are the leading cause of sudden cardiac death, especially in MI. Arrhythmias can be induced by ionic, functional or metabolic abnormalities that occur in response to MI, further characterized by disorder of automaticity, increased heterogeneity of conduction and structural remodeling [4,5].
Several studies have suggested that miR-1 is involved in different aspects of cardiac excitability. In cardiac conduction, miR-1 represses GJA1 (connexin 43), in cardiac automaticity it targets HCN2 and HCN4, in cardiac repolarization it represses KCNA5, KCNE1, KCND2 and KCNJ2 (Kir2.1), and in cardiac depolarization targets CACNA1C [2,6,7]. In contrast, miR-133 is believed to control cardiac repolarization through targeting KCNH2 (HERG) and KCNQ1, although there is evidence to suggest that it also regulates cardiac conduction and automaticity by targeting HCN2 [2,6,8]. miR-208a is believed to be involved, among other functions, also in cardiac conduction by targeting GATA4 and connexin 40 [2,9,10]. All three miRNAs (miR-1, miR-133a/b and miR-208) have recently been related to structural remodeling leading to arrhythmias in canine heart failure [11].
There are numerous publications about the role of myo-miRs, miR-1, miR-133a/b and miR-208a, in MI as well as in arrhythmias [1,2,4,5,12,13]. However, in humans, there are limited data about their contribution in ventricular fibrillation (VF) after MI, in either infarcted or remote myocardium [13]. We hypothesized that deregulation of miR-1, miR-133a/b and miR-208a in MI patients observed in previous studies [14,15] might contribute to the development of VF after MI. We therefore analyzed their expression 24 h after MI and 2–7 days after MI within both infarcted and remote myocardium of patients with and without clinically proven VF.
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Patients and tissue selection
Our study included autopsy samples of infarcted heart tissue and viable border zone, as well as from remote myocardium, from 47 patients with ST-elevation MI, 23 with and 24 without clinically proven VF. The diagnosis of MI was clinically based on symptoms and electrocardiographic changes, and confirmed by elevated plasma levels of troponin I. The duration of MI at the time of death was estimated on the basis of histological changes and clinical data, and patients were divided into two groups:
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Patients, control group and qPCR measurements
All patients’ characteristics are included in Table 1. The age of the 23 patients with MI with clinically proven VF ranged from 35 to 80 years (average 62.0 ± 11.4) and of the 24 patients with MI without clinically proven VF from 59 to 94 (average 75.0 ± 9.0). The control group consisted of 8 trauma victims (5 females and 3 males, aged 18–35, average 26.0 ± 6.0). In Table 2, we present the average Cq ± SD measurements among analyzed groups of samples. The highest Cq values were observed for
Discussion
Muscle- and cardiac-specific miRNAs, miR-1, miR-133a/b and miR-208a, have already been described as deregulated in human MI in our previous studies [14,15]. However, although numerous studies have investigated their role in atrial fibrillation and other arrhythmias, their potential contribution to VF in humans has not yet been investigated. To the best of our knowledge, we describe here for the first time the expression of miR-1, miR-133a/b and miR208a in infarcted and remote myocardium of
Conclusion
Although our study lacks mechanistic insight of exact miR-133a/b targets [7], our results indicate that down-regulation of miR-133a/b may be a hallmark of development of VF after MI in humans. In the future, it might also be a potential therapeutic target for preventing life-threating VF after MI. Furthermore, up-regulation of miR-1 and miR-208 in remote myocardium might have a role in post-MI remodeling, being involved in, among other pathological processes, further myocyte loss. They might
Disclosures
Conflict of interest: none.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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