Inhibition of Rac1 reduces store overload-induced calcium release and protects against ventricular arrhythmia

J Cell Mol Med. 2016 Aug;20(8):1513-22. doi: 10.1111/jcmm.12840. Epub 2016 May 25.

Abstract

Rac1 is a small GTPase and plays key roles in multiple cellular processes including the production of reactive oxygen species (ROS). However, whether Rac1 activation during myocardial ischaemia and reperfusion (I/R) contributes to arrhythmogenesis is not fully understood. We aimed to study the effects of Rac1 inhibition on store overload-induced Ca(2+) release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1(f/f) and cardiac-specific Rac1 knockdown (Rac1(ckd) ) mice were subjected to myocardial I/R and their electrocardiograms (ECGs) were monitored for ventricular arrhythmia. Myocardial Rac1 activity was increased and ventricular arrhythmia was induced during I/R in Rac1(f/f) mice. Remarkably, I/R-induced ventricular arrhythmia was significantly decreased in Rac1(ckd) compared to Rac1(f/f) mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R-induced ventricular arrhythmia. Ca(2+) imaging analysis showed that in response to a 6 mM external Ca(2+) concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca(2+) waves in Rac1(f/f) cardiomyocytes. Notably, SOICR was diminished by pharmacological and genetic inhibition of Rac1 in adult cardiomyocytes. Moreover, I/R-induced ROS production and ryanodine receptor 2 (RyR2) oxidation were significantly inhibited in the myocardium of Rac1(ckd) mice. We conclude that Rac1 activation induces ventricular arrhythmia during myocardial I/R. Inhibition of Rac1 suppresses SOICR and protects against ventricular arrhythmia. Blockade of Rac1 activation may represent a new paradigm for the treatment of cardiac arrhythmia in ischaemic heart disease.

Keywords: Rac1; arrhythmia; ischaemia and reperfusion; reactive oxygen species; store overload-induced calcium release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism*
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / prevention & control*
  • Calcium / metabolism*
  • Electrocardiography
  • Gene Knockdown Techniques
  • Heart Rate
  • Heart Ventricles / pathology*
  • Mice, Inbred C57BL
  • Myocardial Reperfusion
  • Myocytes, Cardiac / metabolism
  • Oxidation-Reduction
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Superoxides / metabolism
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Superoxides
  • rac1 GTP-Binding Protein
  • Calcium