Open AccessInhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia
Author(s) -
Zhang Lili,
Lu Xiangru,
Gui Le,
Wu Yan,
Sims Stephen M.,
Wang Guoping,
Feng Qingping
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12840
Subject(s) - rac1 , medicine , ryanodine receptor , chemistry , calcium , cardiology , pharmacology , endocrinology , signal transduction , biochemistry
Rac1 is a small GTP ase 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 ( ECG s) 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 NSC 23766 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.