MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death
Arin B. Aurora, Ahmed I. Mahmoud, Xiang Luo, Brett A. Johnson, Eva van Rooij, Satoshi Matsuzaki, Kenneth M. Humphries, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, Eric N. Olson
Arin B. Aurora, Ahmed I. Mahmoud, Xiang Luo, Brett A. Johnson, Eva van Rooij, Satoshi Matsuzaki, Kenneth M. Humphries, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, Eric N. Olson
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Research Article Cardiology

MicroRNA-214 protects the mouse heart from ischemic injury by controlling Ca2+ overload and cell death

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.

Authors

Arin B. Aurora, Ahmed I. Mahmoud, Xiang Luo, Brett A. Johnson, Eva van Rooij, Satoshi Matsuzaki, Kenneth M. Humphries, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, Eric N. Olson

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Figure 6

miR-214 is required to maintain efficient Ca2+ handling.

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miR-214 is required to maintain efficient Ca2+ handling. (A) Represe...
(A) Representative Ca2+ traces obtained from isolated WT or miR-214 KO cardiomyocytes. Myocytes were imaged in the presence of 1.8 mM or 5.0 mM extracellular Ca2+. n = 15–20 cells, with 3–5 animals per group for all experiments. (B) Quantitative analyses of intracellular Ca2+ levels shown as corrected average peak Ca2+ transients in WT and miR-214 KO cardiomyocytes in 1.8 mM or 5.0 mM extracellular Ca2+ (top). Ca2+ transient decay shown as τ (seconds) comparing WT and KO at 1.8 mM and 5.0 mM extracellular Ca2+ (bottom). All data are mean ± SEM; ***P < 0.0001.