title: 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.affiliation: Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Arin B
authors.initials: AB
authors.lastname: Aurora
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Brett A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuzaki
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Humphries
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D035683:MicroRNAs; C534781:Mirn214 microRNA, mouse; C559947:Mirn214 microRNA, rat; C499849:NCX1 protein, mouse; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger