MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca 2+ overload and cell death

Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 03/2012; 122(4):1222-32. DOI: 10.1172/JCI59327
Source: PubMed


Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca²⁺ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca²⁺ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca²⁺ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca²⁺ influx; and to repression of several downstream effectors of Ca²⁺ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury.

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Available from: Ahmed I Mahmoud, Oct 01, 2015
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    • "Indeed, in some cases the phenotypic effects of the miRNA deletion only became apparent after the organism is exposed to environmental stress. For example, miR-214 was shown to be a marker of cardiac stress [20], yet knocking out miR-214 in mice had no effect on physiology under normal conditions [21]. However, when these mice were stressed by ischemia/reperfusion injury they exhibited increased apoptosis of cardiac cells and decreased overall survival [21]. "
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    ABSTRACT: Organisms are often exposed to environmental pressures that affect homeostasis, so it is important to understand the biological basis of stress-response. Various biological mechanisms have evolved to help cells cope with potentially cytotoxic changes in their environment. miRNAs are small non-coding RNAs which are able to regulate mRNA stability. It has been suggested that miRNAs may tip the balance between continued cytorepair and induction of apoptosis in response to stress. There is a wealth of data in the literature showing the effect of environmental stress on miRNAs, but it is scattered in a large number of disparate publications. Meta-analyses of this data would produce added insight into the molecular mechanisms of stress-response. To facilitate this we created and manually curated the miRStress database, which describes the changes in miRNA levels following an array of stress types in eukaryotic cells. Here we describe this database and validate the miRStress tool for analysing miRNAs that are regulated by stress. To validate the database we performed a cross-species analysis to identify miRNAs that respond to radiation. The analysis tool confirms miR-21 and miR-34a as frequently deregulated in response to radiation, but also identifies novel candidates as potentially important players in this stress response, including miR-15b, miR-19b, and miR-106a. Similarly, we used the miRStress tool to analyse hypoxia-responsive miRNAs. The most frequently deregulated miRNAs were miR-210 and miR-21, as expected. Several other miRNAs were also found to be associated with hypoxia, including miR-181b, miR-26a/b, miR-106a, miR-213 and miR-192. Therefore the miRStress tool has identified miRNAs with hitherto unknown or under-appreciated roles in the response to specific stress types. The miRStress tool, which can be used to uncover new insight into the biological roles of miRNAs, and also has the potential to unearth potential biomarkers for therapeutic response, is freely available at
    PLoS ONE 11/2013; 8(11):e80844. DOI:10.1371/journal.pone.0080844 · 3.23 Impact Factor
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    • "To identify novel regulators of Ca 2+ overload-mediated cardiac apoptosis, we investigated whether miRNAs are involved in Ca 2+ overload in oxidative stress-induced cardiomyocyte apoptosis. It has been reported previously that miR-214 represses Ca 2+ overload and cell death during IR, and targets NCX1, BIM, CaMKIId, and Cyclophilin D (CypD) [29]. To determine which miRNA was closely related with CaMKIId in Ca 2+ overload, we selected 6 candidate miRNAs that potentially target CaMKIId. "
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    ABSTRACT: A change in intracellular free calcium (Ca(2+)) is a common signaling mechanism of reperfusion-induced cardiomyocyte death. Calcium/calmodulin dependent protein kinase II (CaMKII) is a critical regulator of Ca(2+) signaling and mediates signaling pathways responsible for functions in the heart including hypertrophy, apoptosis, arrhythmia, and heart disease. MicroRNAs (miRNA) are involved in the regulation of cell response, including survival, proliferation, apoptosis, and development. However, the roles of miRNAs in Ca(2+)-mediated apoptosis of cardiomyocytes are uncertain. Here, we determined the potential role of miRNA in the regulation of CaMKII dependent apoptosis and explored its underlying mechanism. To determine the potential roles of miRNAs in H2O2-mediated Ca(2+) overload, we selected and tested 6 putative miRNAs that targeted CaMKIIδ, and showed that miR-145 represses CaMKIIδ protein expression and Ca(2+) overload. We confirmed CaMKIIδ as a direct downstream target of miR-145. Furthermore, miR-145 regulates Ca(2+)-related signals and ameliorates apoptosis. This study demonstrates that miR-145 regulates reactive oxygen species (ROS)-induced Ca(2+) overload in cardiomyocytes. Thus, miR-145 affects ROS-mediated gene regulation and cellular injury responses.
    Biochemical and Biophysical Research Communications 05/2013; 435(4). DOI:10.1016/j.bbrc.2013.05.050 · 2.30 Impact Factor
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    • "In mice, miR-214 expression in cardiac myocyte was up-regulated during ischemic injury, but its change in circulating level was not examined.[11] However, recent studies demonstrate that miRNAs can be delivered by apoptotic bodies to atherosclerotic lesion.[12] In addition, miRNAs can also be transferred between different cells by exosomes[13] or lipoproteins.[14] "
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    ABSTRACT: To study whether miR-214 is regulated in coronary artery disease (CAD) patients and whether placental growth factor (PLGF) is a possible target for miR-214 in atherosclerosis. Circulating miR-214 was measured by quantitative PCR using RNA isolated from 40 patients with CAD, including 12 with stable angina pectoris, 16 with unstable angina pectoris and 12 with acute myocardial infarction, and 15 controls without CAD. Plasma level of PLGF was measured by ELISA. The miR-214 level was significantly lower in CAD patients compared with that in controls (P < 0.01). Compared to controls, patients with unstable angina pectoris (UAP, 38.6±9.1 pg/mL) and acute myocardial infarction (AMI, 46.3±13.4 pg/mL) had significantly higher level of plasma PLGF, but not those with stable angina pectoris (SAP; P = 0.012, UAP vs. Control; P = 0.005, AMI vs. Control). In patients with AMI, the plasma level of miR-214 was positively correlated to that of PLGF. The results suggest that miR-214 is a beneficial microRNA for CAD patients. Loss of its protection may lead to increased PLGF levels and worsening atherosclerosis. Circulating miR-214 is a promising biomarker for alerting severe CAD.
    Journal of Geriatric Cardiology 03/2013; 10(1):34-8. DOI:10.3969/j.issn.1671-5411.2013.01.007 · 1.40 Impact Factor
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