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

J Clin Invest. 2012 Apr;122(4):1222-32. doi: 10.1172/JCI59327. Epub 2012 Mar 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Calcium Signaling / physiology*
  • Cells, Cultured / metabolism
  • Gene Deletion
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Mice
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Mitochondria / physiology
  • Myocardial Contraction / physiology
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Calcium Exchanger / biosynthesis
  • Sodium-Calcium Exchanger / genetics

Substances

  • MicroRNAs
  • Mirn214 microRNA, mouse
  • Mirn214 microRNA,rat
  • NCX1 protein, mouse
  • RNA, Messenger
  • Sodium-Calcium Exchanger