MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca²⁺ 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: 15.39). 03/2012; 122(4):1222-32. DOI: 10.1172/JCI59327
Source: PubMed

ABSTRACT 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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    Frontiers in Cell and Developmental Biology 10/2014; 2:61. DOI:10.3389/fcell.2014.00061
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    ABSTRACT: Electroacupuncture pretreatment plays a protective role in myocardial ischemia/reperfusion (I/R) injury and microRNAs (miRNAs) could act on various facets of cardiac function. However, the role of miRNAs in the cardioprotection by electroacupuncture pretreatment on myocardial I/R injury remains unknown. The purpose of the study was to examine whether miR-214 was involved in cardioprotection by electroacupuncture. Using rat myocardial I/R model, we examined the role of electroacupuncture pretreatment in myocardial I/R injury and analyzed the changes in the expression of miR-214. In addition, I/R was simulated in vitro by performing oxygen-glucose deprivation (OGD) on H9c2 cell cultures, and the effect of electroacupuncture pretreatment on I/R injury as well as expressional level of miR-214 were examined in vitro. Furthermore, the miR-214 mimic was transfected into OGD-treated H9c2 cells, we analyzed the cell apoptosis, lactate dehydrogenase (LDH) and creatine kinase (CK) activities, intracellular free Ca(2+) concentration ([Ca(2+)]i) as well as the relative protein levels of sodium/calcium exchanger 1(NCX1), BCL2-like 11 (BIM), calmodulin-dependent protein kinase IIδ (CaMKIIδ) and Cyclophilin D (CypD). The in vivo results revealed that compared with the I/R group, the electroacupuncture pretreatment group showed significant decreased myocardial infarct size, as well as the increased indices of the cardiac function, including heart rate, mean arterial pressure, left ventricular systolic pressure and maximal rate for left ventricular pressure rising and declining (±dp/dt max). In addition, electroacupuncture pretreatment could inhibit the elevation of LDH and CK activities induced by I/R injury. The quantitative PCR (qPCR) results demonstrated electroacupuncture pretreatment could provide cardioprotection against myocardial I/R injury in rats with miR-214 up-regulation. In the meanwhile, in vitro, electroacupuncture pretreatment protected H9c2 cells from OGD-induced injury. Transfection of miR-214 mimic showed protective effects on OGD-induced injury to H9c2 cells by reducing apoptosis, decreasing LDH and CK activities, rescuing the OGD-induced Ca(2+) and down-regulating elevated protein levels of NCX1, BIM, CaMKIIδ and CypD. Our findings firstly demonstrated that electroacupuncture pretreatment promotes the expression of miR-214 in myocardial I/R injury and miR-214 contributes to the protective effect of electroacupuncture on myocardial I/R injury.


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Jun 2, 2014