MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

JCI Insight. 2020 Dec 3;5(23):e140759. doi: 10.1172/jci.insight.140759.

Abstract

Cardiac ischemia is associated with arrhythmias; however, effective therapies are currently limited. The cardiac voltage-gated sodium channel α subunit (SCN5A), encoding the Nav1.5 current, plays a key role in the cardiac electrical conduction and arrhythmic risk. Here, we show that hypoxia reduces Nav1.5 through effects on a miR, miR-448. miR-448 expression is increased in ischemic cardiomyopathy. miR-448 has a conserved binding site in 3'-UTR of SCN5A. miR-448 binding to this site suppressed SCN5A expression and sodium currents. Hypoxia-induced HIF-1α and NF-κB were major transcriptional regulators for MIR448. Moreover, hypoxia relieved MIR448 transcriptional suppression by RE1 silencing transcription factor. Therefore, miR-448 inhibition reduced arrhythmic risk after myocardial infarction. Here, we show that ischemia drove miR-448 expression, reduced Nav1.5 current, and increased arrhythmic risk. Arrhythmic risk was improved by preventing Nav1.5 downregulation, suggesting a new approach to antiarrhythmic therapy.

Keywords: Arrhythmias; Cardiology; Sodium channels; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antagomirs / metabolism
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / prevention & control
  • Gene Expression Regulation / genetics
  • Heart Rate / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Ischemia / genetics*
  • Myocardial Ischemia / metabolism
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Sodium / metabolism

Substances

  • Antagomirs
  • MIRN448 microRNA, human
  • MIRN448 microRNA, mouse
  • MicroRNAs
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium