Mutual antagonism between IP3RII and miRNA-133a regulates calcium signals and cardiac hypertrophy

Babraham Institute, Babraham, Cambridge CB22 3AT, England, UK.
The Journal of Cell Biology (Impact Factor: 9.83). 11/2012; 199(5). DOI: 10.1083/jcb.201111095
Source: PubMed


Inositol 1,4,5'-triphosphate receptor II (IP(3)RII) calcium channel expression is increased in both hypertrophic failing human myocardium and experimentally induced models of the disease. The ectopic calcium released from these receptors induces pro-hypertrophic gene expression and may promote arrhythmias. Here, we show that IP(3)RII expression was constitutively restrained by the muscle-specific miRNA, miR-133a. During the hypertrophic response to pressure overload or neurohormonal stimuli, miR-133a down-regulation permitted IP(3)RII levels to increase, instigating pro-hypertrophic calcium signaling and concomitant pathological remodeling. Using a combination of in vivo and in vitro approaches, we demonstrated that IP(3)-induced calcium release (IICR) initiated the hypertrophy-associated decrease in miR-133a. In this manner, hypertrophic stimuli that engage IICR set a feed-forward mechanism in motion whereby IICR decreased miR-133a expression, further augmenting IP(3)RII levels and therefore pro-hypertrophic calcium release. Consequently, IICR can be considered as both an initiating event and a driving force for pathological remodeling.

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Available from: Chihiro Hisatsune,
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    • "Drawnel and collaborators have described an interesting mutual antagonism between inositol 1,4,5′-triphosphate receptor II (IP3RII) calcium channel and miRNA-133a. This antagonism regulates calcium signals and cardiac hypertrophy (Drawnel et al., 2012). Indeed, IP3RII expression is increased in hypertrophic failing human myocardium. "
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    ABSTRACT: Researchers and clinicians have discovered several important concepts regarding the mechanisms responsible for increased risk of arrhythmias, heart failure, and sudden cardiac death. One major step in defining the molecular basis of normal and abnormal cardiac electrical behavior has been the identification of single mutations that greatly increase the risk for arrhythmias and sudden cardiac death by changing channel-gating characteristics. Indeed, mutations in several genes encoding ion channels, such as SCN5A, which encodes the major cardiac Na(+) channel, have emerged as the basis for a variety of inherited cardiac arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction disorder, sinus node dysfunction, or sudden infant death syndrome. In addition, genes encoding ion channel accessory proteins, like anchoring or chaperone proteins, which modify the expression, the regulation of endocytosis, and the degradation of ion channel a-subunits have also been reported as susceptibility genes for arrhythmic syndromes. The regulation of ion channel protein expression also depends on a fine-tuned balance among different other mechanisms, such as gene transcription, RNA processing, post-transcriptional control of gene expression by miRNA, protein synthesis, assembly and post-translational modification and trafficking. The aim of this review is to inventory, through the description of few representative examples, the role of these different biogenic mechanisms in arrhythmogenesis, HF and SCD in order to help the researcher to identify all the processes that could lead to arrhythmias. Identification of novel targets for drug intervention should result from further understanding of these fundamental mechanisms.
    Frontiers in Physiology 09/2013; 4:254. DOI:10.3389/fphys.2013.00254 · 3.53 Impact Factor
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    • "Conversely, miR‐133a upregulation can counteract Caspase9‐mediated apoptosis upon myocardial injury.46 Moreover, miR‐133a downregulation has been recently shown to further worsen prohypertrophic calcium signaling and pathological remodeling in the heart.47 However, changes in global miRNA levels could theoretically lead to adverse side events (eg, high miR‐133a levels have been associated with retinal degeneration).48 "
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    ABSTRACT: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM.
    Journal of the American Heart Association 07/2013; 2(4):e000284. DOI:10.1161/JAHA.113.000284 · 4.31 Impact Factor
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    • "Down‐regulation of miR‐133 is related to the hypertrophic growth of cultured cardiomyocytes.16,18–20,22 Also, the pathological hypertrophic growth and extracellular matrix remodeling of the heart that occurs in response to pathological signaling is under the control of miR‐133, both in mouse experimental models17–19,23,29 and in human pathologies.17,24,30 Thus, it appears that miR‐133 plays a key role in the control of the trophic state of the heart under normal conditions and that, when miR‐133 is down‐regulated (such as in the pressure overload condition), the transcriptional derepression of genes encoding proteins that regulate cardiac structure likely contributes to the adverse remodeling response. "
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    ABSTRACT: Myocardial microRNA-133a (miR-133a) is directly related to reverse remodeling after pressure overload release in aortic stenosis patients. Herein, we assessed the significance of plasma miR-133a as an accessible biomarker with prognostic value in predicting the reversibility potential of LV hypertrophy after aortic valve replacement (AVR) in these patients. The expressions of miR-133a and its targets were measured in LV biopsies from 74 aortic stenosis patients. Circulating miR-133a was measured in peripheral and coronary sinus blood. LV mass reduction was determined echocardiographically. Myocardial and plasma levels of miR-133a correlated directly (r=0.46, P<0.001) supporting the myocardium as a relevant source of plasma miR-133a. Accordingly, a significant gradient of miR-133a was found between coronary and systemic venous blood. The preoperative plasma level of miR-133a was higher in the patients who normalized LV mass 1 year after AVR than in those exhibiting residual hypertrophy. Logistic regression analysis identified plasma miR-133a as a positive predictor of the hypertrophy reversibility after surgery. The discrimination of the model yielded an area under the receiver operator characteristic curve of 0.89 (P<0.001). Multiple linear regression analysis revealed plasma miR-133a and its myocardial target Wolf-Hirschhorn syndrome candidate 2/Negative elongation factor A as opposite predictors of the LV mass loss (g) after AVR. Preoperative plasma levels of miR-133a reflect their myocardial expression and predict the regression potential of LV hypertrophy after AVR. The value of this bedside information for the surgical timing, particularly in asymptomatic aortic stenosis patients, deserves confirmation in further clinical studies.
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