MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

Abstract

The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.

Potential roles of microRNA-1 and microRNA-133 in cardiovascular disease

“…But, in reviewing their roles and mechanisms in cardiovascular pathophysiology, we observed that both miR-1 and miR-133 change in the same ways during arrhythmia, myocardial infarction, diabetic cardiomyopathy, myocardial hypertrophy, and cardiomyocyte dif-ferentiation. Therefore, it has subsequently been further confirmed that miR-1 and miR-133 do not exist independently, but act as two associated co-transcriptional and cooperative regulatory factors (Besser et al, 2014;Wystub et al, 2013). Furthermore, we also found that miR-1 and miR-133 participate in pathophysiological cardiac processes and play cardioprotective roles through a variety of means.…”

MicroRNAs in heart failure: from biomarker to target for therapy

“…Disturbances in the β‐adrenergic signalling pathway can lead to a longQT phenotype in single miR‐1/133 cluster knockout mice. Moreover, prolonged action potentials were found in cardiomyocytes with a deletion of miR‐1/133a, suggesting that this miRNA cluster is essential for normal electrophysiology in the heart . Matkovich et al demonstrated that miR‐133 had protective effects in miR‐133 transgenic mice undergoing TAC.…”

“…Moreover, prolonged action potentials were found in cardiomyocytes with a deletion of miR-1/133a, suggesting that this miRNA cluster is essential for normal electrophysiology in the heart. 85 Matkovich et al 86 demonstrated that miR-133 had protective effects in miR-133 transgenic mice undergoing TAC. They observed stable levels of miR-133, a significant decrease in myocardial fibrosis, improvement in diastolic function, and no development of hypertrophy.…”

Possible tumor suppressive role of the miR-144/451 cluster in esophageal carcinoma as determined by principal component regression analysis

“…Previous studies have demonstrated that clustered miRNAs may mediate cooperative functions by targeting the same or multiple genes simultaneously (15,16,47). Using bioinformatics analyses, the potential common or similar molecular functions of miR-144-3p, miR-144-5p and miR-451a, which are aberrantly expressed in tumor tissues, were explored in the current study.…”

“…An increasing number of studies have demonstrated that miRNA clusters serve important roles in certain biological processes and during oncogenesis (10)(11)(12)(13). A few well-studied miRNA clusters include the miR-17/92, miR-221/222 and miR-1/133a clusters (14)(15)(16). Additional studies have demonstrated that miRNA clusters function more efficiently compared with individual miRNAs alone.…”